Wittig rearrangement ethers

The rearrangement of an ether 1 when treated with a strong base, e.g. an organo-lithium compound RLi, to give an alcohol 3 via the intermediate a-metallated ether 2, is called the Wittig rearrangement. The product obtained is a secondary or tertiary alcohol. R R can be alkyl, aryl and vinyl. Especially suitable substrates are ethers where the intermediate carbanion can be stabilized by one of the substituents R R e.g. benzyl or allyl ethers. 

A proton can be removed from an allylic ether by treatment with an alkyllithium at about -70°C [at higher temperatures the Wittig rearrangement (18-22) takes place] to give the ion 130, which reacts with alkyl halides to give the two products... 

An earlier example of this type of domino reaction was reported by Greeves and coworkers (Scheme 2.194) [443]. Treatment of either the ( )- or (Z)- allyl vinyl ether 2-870 with NaH initiates the [2,3]-Wittig rearrangement to afford 2-872 via 2-871. The subsequent oxy-Cope rearrangement led to the aldehyde 2-873, which was reduced with NaBH4 to give the alcohols 2-874. Both isomers of 2-870 predominantly generated the (/ )-xyu-product 2-874 in comparable ratios as the main product. 

In order to establish the correct absolute stereochemistry in cyclopentanoid 123 (Scheme 10.11), a chirality transfer strategy was employed with aldehyde 117, obtained from (S)-(-)-limonene (Scheme 10.11). A modified procedure for the conversion of (S)-(-)-limonene to cyclopentene 117 (58 % from limonene) was used [58], and aldehyde 117 was reduced with diisobutylaluminium hydride (DIBAL) (quant.) and alkylated to provide tributylstannane ether 118. This compound underwent a Still-Wittig rearrangement upon treatment with n-butyl lithium (n-BuLi) to yield 119 (75 %, two steps) [59]. The extent to which the chirality transfer was successful was deemed quantitative on the basis of conversion of alcohol 119 to its (+)-(9-methyI mande I ic acid ester and subsequent analysis of optical purity. The ozonolysis (70 %) of 119, protection of the free alcohol as the silyl ether (85 %), and reduction of the ketone with DIBAL (quant.) gave alcohol 120. Elimination of the alcohol in 120 with phosphorus oxychloride-pyridine... 

For allyl ethers 790 with R1 =Ph, treatment with LDA generates anions 791 which undergo [2,3]-Wittig rearrangement to more stable alkoxides 792 (Scheme 126). Spontaneous expulsion of benzotriazole anion from 792 generates (3,y-unsaturated ketones 793 that are isolated in high yields (86-92%) <1996JOC4035>. In the case of... 

The application of RCM to dihydropyran synthesis includes a route to 2,2-disubstituted derivatives from a-hydroxycarboxylic acids. In a one-pot reaction, the hydroxy esters undergo sequential O-allylation, a Wittig rearrangement and a second O-allylation to form allyl homoallyl ethers 8. A single RCM then yields the 3,6-dihydro-2//-pyran 9. The process is readily adapted not only to variably substituted dihydropyrans but also to 2-dihydrofuranyl and 2-tetrahydrooxepinyl derivatives and to spirocycles e.g. 10 through a double RCM (Scheme 4) <00JCS(P1)2916>. 

Nevertheless, another possibility remained for the formation of insertion products, that they might be formed from the O-H insertion product, e.g., dichloromethyl benzyl ether 5, by the Wittig rearrangement of dichloromethoxy-carbanion 4, (Scheme 5, Eq. I).17 However, treatment of independently prepared benzyl dichloromethyl ether 5 with the same base solely gave benzyl chloride, but the insertion product was not obtained (Eq. 2). Hence, a Wittig-type rearrangement process was excluded. 

The bis(oxazoline) S, 5)-(115) has been used as an external chiral ligand to induce asymmetric diastereoselective lithiation by r-BuLi during [2,3]-Wittig rearrangement of achiral substrates, (fj-crotyl propargylic ethers.It is believed that the enantios-electivity is determined predominantly at the lithiation step. 

Transformation of allyl ethers into homoallylic alcohols by treatment with base. Also known as Still-Wittig rearrangement. Cf. Sommelet-Hauser rearrangement... 

One of the most important side reactions often observed with the [1,2]-Wittig rearrangement is the a,/3 -elimination (equation 3). In fact, treatment of benzyl ether 3 with n-BuLi afforded predominantly the elimination product 4 (equation A f. 

The acetal [1,2]-Wittig rearrangement protocol is also applicable to the synthesis of medium-sized cyclic ethers. For example, a reaction of the 9-membered cyclic acetal 37 with lithium piperidide provides the 8-membered ring ether 38 in good yield along with high diastereoselectivity (equation 20) . 

Miscellaneous The treatment of allyl 1-bromo-2-naphthyl ether 43 with f-BuLi affords benzyl alcohol 44 via a sequential reaction consisting of bromine-lithium exchange, and anion translocation, followed by a [1,2]-Wittig rearrangement (equation 23). ... 

The pioneering work on enantioselective [2,3]-Wittig rearrangement was carried out by Marshall and Lebreton in the ring-contracting rearrangement of a 13-membered cyclic ether using lithium bis(l-phenylethyl) amide (63) as a chiral base (equation 34). Upon treatment with a (S,S)-63 (3 equivalents) in THF at —70 to —15 °C, ether 64 afforded the enantioenriched [2,3]-product 65 in 82% yield with 69% ee. The reaction was applied in the synthesis of (+)-aristolactone (66). 

A high level of enantioselectivity in an acyclic system has been reported in the rearrangement of tricarbonylchromium(O) complexes of allyl benzyl ethers using chiral lithium amide base 73 (equation 38) . Upon treatment with 1.1 equivalents of lithium amide 73 and 1 equivalent of LiCl at —78 to —50°C, ether 74 afforded the rearrangement product R)-75 in 80% yield with 96% ee. The effect of substituents on the chemical yields and enantioselectivity of the [2,3]-Wittig rearrangement was also studied (see Table 3). 

Norpseudoephedrine-derived amino ether 81 was also used as a chiral coordinating agent for the enantioselective [2,3]-Wittig rearrangement. The rearrangement of propargyl ether 82 induced by n-BuLi/81 provided allenyl alcohol (5 )-83 in 62% ee (equation 45). In contrast, a similar reaction with (-)-24 provided only 9% ee of (S)-S3. 

Chiral bis(oxazoline) 27 is an effective chiral coordinating agent for enantiocontrol in the [2,3]-Wittig rearrangement. The rearrangement of (Z)-crotyl benzyl ether 84 with f-BuLi/(5, 5)-27 (1.5 equivalents each) in hexane provided [2,3]-shift product (l/ ,25 )-85 in 40% ee (equation 46The feasibility of the asymmetric catalytic version was also examined. In this case, the rearrangement with 20 mol% of 27 in ether was found to provide the same level of enantioselectivity (34% ee). 

TABLE 4. [1,4]-Wittig rearrangement of propargyl ether systems... 

Taylor and colleagues have shown the sequential carbolithiation/[l,4]-Wittig rearrangement of styryl ethers 105 (e.g., 105a) which provide appropriately functionalized 2-alkylphenol 106 (e.g., 106a) in good yield . In this reaction, the alkenyl transfer occurs with retention of configuration (equations 59 and 60). 

As a unique [1,4]-Wittig rearrangement, the transformation of 3-iodoalkyl vinyl ether 107 to the 4-alken-l-ol 108 has been reported by Bailey s group (equation 61, Table 5) . The rearrangement is undoubtedly mediated by a regiospecific 5-cxo-trig ring closure. 

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