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DOI: 10.1055/sos-SD-037-00052

Tsukamoto, M.; Kitamura, M.Science of Synthesis, (20083750.

The original reaction[‌33‌] of alkali metal alkoxides 18 with alkyl halides 19 is still one of the standard protocols for the synthesis of unsymmetrical ethers 20 (e.g., synthesis of 22 from 21, Scheme 8), and has been modified continuously with respect to the generation of alkoxides and solvents or reaction media. Alkoxides are usually prepared by reaction of alcohols with sodium or sodium hydride under reflux.[‌1‌,‌2‌,‌34‌‌38‌] In the case of simple alcohols, such as methanol or ethanol, an excess of alcohol is employed as solvent. Other solvents employed are toluene, xylene, liquid ammonia, ethers, and dimethylformamide. The use of alkyl halides that have no β-hydrogen, such as iodomethane or benzyl halides, affords excellent yields. Alkoxides work not only as nucleophiles, but also as strong bases to promote elimination, which is pronounced in reactions employing secondary or tertiary alkyl, or 2-arylethyl, halides. A preferable combination to minimize this side reaction is the alkoxide derived from the more-substituted alcohol, and the less-substituted alkyl halide. Reactivity of alkyl halides in substitution decreases in the order iodides > bromides > chlorides. Alkyl iodides are more susceptible to elimination than alkyl bromides.[‌1‌,‌2‌]

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Meeeee 88 Meeeeeeeee Meeee Meeeeeeee ee e Meeee Meeeeee[‌88‌]

Meeeeeeeeeee Meeeeeeee

8,8-Mee(eeeeeeeee)eee-8-eee (88); Meeeeee Meeeeeeee:[‌88‌]

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