Ethers, methyl Wittig rearrangement

S ily 1) ally lie ethers 234 readily undergo 2,3-Wittig rearrangement upon treatment with an amide base to give, after methylation, 235 (equation 192)37,343. Tandem Claisen-2,3-Wittig-oxy-Cope rearrangement has been observed when 236 is treated under similar... 

Benzyl methyl ether or allyl methyl ethers can be selectively metalated at the benzylic/allylic position by treatment with BuLi or sBuLi in THF at -40 °C to -80 C, and the resulting organolithium compounds react with primary and secondary alkyl halides, epoxides, aldehydes, or other electrophiles to yield the expected products [187, 252, 253]. With allyl ethers mixtures of a- and y-alkylated products can result [254], but transmetalation of the lithiated allyl ethers with indium yields y-metalated enol ethers, which are attacked by electrophiles at the a position (Scheme 5.29). Ethers with ft hydrogen usually undergo rapid elimination when treated with strong bases, and cannot be readily C-alkylated (last reaction, Scheme 5.29). Metalation of benzyl ethers at room temperature can also lead to metalation of the arene [255] (Section 5.3.11) or to Wittig rearrangement [256]. Epoxides have been lithiated and silylated by treatment with sBuLi at -90 °C in the presence of a diamine and a silyl chloride [257]. 

Still-Wittig rearrangement of the ( )- and (Z)-17-ethylidene-16a ethers (93) and (94) afforded the 20a- and 20p-methyl steroids (95) and (96) with complete stereochemical control (equation 23). As in other examples, sp stereochemistry depends upon double bond geometry in the starting allylic ether. 

The low yield of ortho lithiation, in the above experiments, is presumably due to the formation of the lithio salt of the alcohol in the first instance on treatment with the lithiating agent. Quite often the reaction becomes heterogeneous. A conceivable modification of the above reaction would be lithiation of the corresponding methyl ether derivative. However, in the latter case the reaction takes a different course. The chief reaction now is the formation of the benzylic carbanion which undergoes the Wittig rearrangement When the benzylic position is fully substituted by a carbon residue (such as alkyl or aryl), ortho lithiation occurs in better yield, and further reaction with COj furnishes the 3,3-disubstituted phthalides. 

Methyl ketone 398, which is available from 379 according to procedures previously discussed, has been used as a chiral precursor for rearrangement studies. The requisite substrate 399 is prepared by addition of vinylmagnesium bromide to 398, which produces a tertiary alcohol with > 95% optical purity. Deprotonation of oxazoline ether 399 with Ai-butyllithium results in a [2,3] Wittig rearrangement and furnishes 400 as the sole product [125]. This remote transfer of chirality is of potential use in constructing fragments associated with a variety of macrolides. 

More recently, bisoxazolines were studied as ligands in [2,3]-Wittig rearrangements (up to 89% ee) [46] these ligands were also effective in a catalytic maimer [47]. Bisoxazoline 30 provides remarkably high enantioselectivity in the benzyhc lithiation-electrophile trapping reactions of benzyl methyl ether, iso-chroman and phthalan (up to 97% ee) (e.g.,Scheme 15) [48]. 

At — 65 °C in THF allylic ethers may be metalated with methyl-lithium in high yield without any Wittig rearrangement With n-hexyl iodide the metalated species (227 M = Li) underwent alkylation preferential y to oxygen. However, with cyclohexanone (227 M = Li) gave ratios the inverse of those predicted from alkylation studies. Thus when (227 R = Bu M = Li) reacted widt cyclohexanone, the product... 

Subsequent studies by Wittig demonstrated that deprotonation of benzyl alkyl ether derivatives with phenyllithium could provide the requisite carbanion and induce [1,2]-Wittig rearrangement. For example, treatment of benzyl methyl ether (9) with phenyllithium provided a-methyl benzyl alcohol (10) in 35% yield upon workup. 

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