Science of Synthesis

Tsukamoto, M.; Kitamura, M., Science of Synthesis, (2008) 37, 50.

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.[‌1‌,‌2‌,‌34‌–‌38‌] 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]

‌Meeeee 8‌ Meeeeeee ee Meeeee Meeeeeeee eeee Meeee Meeeee[‌88‌]

Meeeee eeeeeeeeee eeeee eeee eeeee eeeeeee eeee ee eeeee ee eeeeee eeeeeee ee eeeeee eeeee eeeeee eeeeee ee eeeeeeeeeeeeeee, eeeeeeeeeeeeeeeee, ee eeeeeee. Meeeeee eeeeeee eee eeeeeeeeee ee eee eeee ee eeeeee 8-eeeeeeeeeee, eeeee eeeeeeeee eeee M- eee M-eeeeeeeeee (‌Meeeee 8‌), eee eeeee ee eeeee eeeeeee eeee eee eeeeeee’e eeeeeeeeee eeeeee. Meeeeeee ee eeeeeee eeeeeee eeeeeeee eeee ee eeeeeeeeeeeeeeeee ee eeeeeeee eeeeeeeee eeeee eeeeeeeeeeeee M-eeeeeeeeee eeeeeeee eeee ee ‌88‌, eeeeeee eeeeee eeeeeeee eeee ee eeeeeeee ee eeeee eeeeee e eeeeeeeeeee eeeeee ee M-eeeeeeeeee eeeeeeee eeee ee ‌88‌.[‌8‌,‌88‌] Meeeeeeee eeeeeeeee eeeeee eeeeeeeeeeeeeeeeee ee eeeeeeeeeee eeeeeee ee 888 °M ee eeeee, eeeee eeeee eee eeeeeeee ee eeeeeee eeeeeee eeeeeeee, eeee ee eeeeee eeeeeeeeeeeeee M-eeeeeeeeee.[‌88‌] Meeee eeeeee eeeee eee ee eeeeeeeeeeeeee eeeeeeeee eeeee eee eeeeeeee ee eeeeeeeee.

‌Meeeee 8‌ Meeeeeee ee Meeeee 8-Meeeeeeeeee eeee Meeeee Meeeeee[‌88‌,‌88‌]

Mee ee eee eeeeeeeeee eeeeeeeee eeeeee eeeeeeeeee ‌88‌ ee eee eeeeeeee ee (M)-eeeeeeeeeeee eeeeee ee eeeeeee α-eeeee eeeeeeeeee eeeee ‌88‌, eeeee eeeee α-eeeeeee eeeeee ‌88‌ eee ‌88‌ eeee eeeeeeeeeeeeeeeeeeeeee eeeeeee eeee 88:88 ee 88:8 (‌Meeeee 88‌).[‌88‌] Mee eeeeeeee eeeeeeeeeeeee, eeee eeeeeee eeee 88% eeeee ee eee eeeee eeeeeeeeeeee, eeeeeeee eeee eee (8M)-eeeeee eeeeee eeeeee eeee eee (8M)-α-eeee eeeee, eee eeee eeee eeeeeee eee eeeeeeeeeeeeee ee eee eeeeee ee eee eeeeeeee eeeeeee.

‌Meeeee 88‌ Meeeeeeee ee Meeeee Meeeeeeeee eee Meeeeee α-Meeee Meeeee[‌88‌]

Meeee eeeee eeeeeeeee eeee eeeeeee eeeee ee eeeeeee,[‌88‌] eeee,[‌88‌] eeeeee,[‌88‌] eeeeeeee,[‌88‌,‌88‌] eee eee.[‌88‌–‌88‌] Meeeeeee(M) eeeeeeeee ‌88‌ eeeee eee eeeeeeeeeee ee eeeeeeeee eeeeee eeeeee ‌88‌ (‌Meeeee 88‌).[‌88‌] Meee, eeeeeee eeeeee ee eeeeee, eeeee, eee eeeeeeee eeee eeeeeeeeeee eee eeeeeeeee eeeeeee eeeeeeeeeeee ee eeeeeeeeeeeee.

‌Meeeee 88‌ Meeeeeeee ee Meeeeeee(M) Meeeeeeee eee Meeee Meeeeee[‌88‌]

M eeeeeeeeee eeeeeeee eee eeeeeeee eeeee eeee eeeeeeeee, Meeeeeeee MMM-888 (MeM–), ee e eeeee eeeeeee eeee eeeeee eeee eeeeeee eeeee eeeeeee ee 88–88 °M ee eeee eeeeee eeeeee ‌88‌ (‌Meeeee 88‌).[‌88‌] Meeee eeeee-eeeeeeee eeeeee eeeeeee MMM-888 eee Meeee 8-M8.[‌88‌] eeee-Meeee eeeeeee eee eeeeeeee ee eee eeeeeee eeeeeeee.[‌88‌] Mee eeeeee eee ee eeeeee eee eee eeeeeeeee ee eeeeeeeeeeeee eeeeeeeee eeeeeeeeee eeee eee eeeeeee eeeeee.[‌88‌]

‌Meeeee 88‌ M-Meeeeeeeee ee Meeeeee eeee Meeee Meeeeee Meeee Meeeeeeee MMM-888[‌88‌]

Meeeeeeeee eeeeeeeee eeee eeee eeee eee eeeeeeeeeeeeee ee eeeeeeee ee eeeeeee eee eeeee eeeeeee eeeeeeeeee eeeee ee eeeee eeeeeeee eeee ee Meeeeeeeee (eeeeee eeeeee eeee) eee Meee [(eeeeeeeee)eeeeee eeeeee eeee] eeeeee.[‌88‌] Me eeeeeeee ee e eeeee-eeeee ω-eeeeeeeeee eeeeeee eeee ee ‌88‌ eeee eeeeeee eeeeeeeee eeee ee ‌88‌, e eeee eeeeee/eeeeee (>88 eeeee) ee eeeeeeee ee eeeeeeee eee eeeeeeeeeeee/eeeeeeeeeee (‌88‌/‌88‌) eeeee (‌Meeeee 88‌).[‌88‌] Mee ee eeeeeee eeeee eeeeee ee e eeeeee eeeeeeee e eeeeee eeeeeeeeeee ee eeeeee eeee eee ee eee eeeeeee-eeeeee “eeeeeeeee” eeeeee, eeeee eeeeeeeee eeeeeee eeee eee eeeeeeee-eeeee eeeeeeeee. Mee eeeeeee eeeeeeeeeeee/eeeeeeeeeee eeeee ee eeee eeee 88 ee eeeeeeee eeee e eeeeeeeeeee ee e = 88 eee M8 = M.

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

Meeeeeeeeeee Meeeeeeee

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

M eeeeeee ee MeM (8.8 eeeee) ee eee MMM eee eeeeee ee 8 °M. M 8.8 M eeee ee eee-8-eee-8,8-eeee (‌88‌) ee eee MMM (8 eeeee) eee eeeee eeeeee eee eee eeee eee eeeeeee ee 8 °M eee 8 e. Meee, 8.8 M MeMe ee eee MMM (8.88 eeeee) eee eeeee. Mee eeee eee eeeeee ee 88 °M eeeee eeee eeeeeeeeee eee eeeeeeee (88–88 e). Mee eeeeeee eee eeeeeee eeeee eeeeeee eeeeeeee eee eee eeeee eeeeeeee eee eeeeeeee ee eeeee eeeeeeeeeeeeee (eeeeee eee, eeeeeee/MM8Me8) ee eeeeee eee eeeeeee; eeeee: 88%.

References

Meeeeee Meeeeeeeeee

• 8.Meeeee-Meee, (8888) 8/8, 88.
• 8.Meeeee-Meee, (8888) 8/8e, 888.
• 8.Meeeee-Meee, (8888) M 88e8, 888.