Methoxy-substituted benzyl ethers

Several methoxy-substituted benzyl ethers have been prepared and used as protective groups. Their utility lies in the fact that they are more readily cleaved oxidatively than the unsubStituted benzyl ethers. The table below gives the relative rates of cleavage with dichlorodicyanoquinone (DDQ). ... 

In the complexes of w/Ao-substituted benzyl ethers, the benzylic hydrogen atoms are diastereotopic. Alkylation of the derived lithium compounds occurs completely stereoselective-ly anti to the tricarbonylchromium face from a rotamer in which the benzylic methoxy group is anti to the or/Ao-substituent2,3. The stereochemistry of the alkylation was confirmed unambiguously by X-ray analysis of the product3. 

The additional presence of a 3-methoxy substituent on the benzyl group confers greater stability on the intermediate cation, and consequently oxidation of DMPM ethers by DDQ is even more facile. Yonemitsu and cowoikers have used this differential reactivity of substituted benzyl ethers to great effect in the total synthesis of the macrolide antibiotics methynolide, tylonolide, (95)-9-dihydroerythro-nolide and pikronolide. The pikronolide synthesis provides an excellent example of the selective, sequential deprotection of DMPM, MPM and benzyl ether protecting groups (Scheme 7). 

Ten years later, a Japanese group led by Oikawa developed a mechanistically related method for the selective debenzylation of substituted benzyl ethers based on the reagent 2,3-dichloro-S,6-dicyanobenzo-quinone (DDQ). In contrast to the trityl tetrafluoroborate reaction, the oxidation proceeds at room temperature in the presence of water. Furthermore, under these convenient and essentially neutral conditions, many functional groups, including other common protecting groups, such as isopropylidine, methoxy-methyl, benzyloxymethyl, tetrahydropyranyl, acetyl, r-butyldimethylsilyl, benzyl, benzoyl and tosyl, are unaffected. As a result of the hig levels of selectivity which can be achieved, this method for the depro-... 

Preparation of Benzyl Chlorides. A 5.0 g sample (0.015-0.025 mol) of methoxy substituted benzyl alcohol in 100 mL benzene was added to a 250 mL round bottom flask. With constant stirring, 3.0 ml (1-1.5 mol relative to the benzyl alcohol) thionyl chloride was added dropwise over a period of 30 min. The reaction mixture was refluxed, and then transferred into a 500 ml beaker containing 200 ml 10% sodium hydroxide solution. The solution was extracted with ethyl ether. The combined organic layers were washed with 10% sodium carbonate solution followed by saturated brine, then dried with anhydrous sodium sulfate, and concentrated to give the crude product. Finally, column chromatography eluted with benzene afforded the spectroscopically pure benzyl chloride as a white solid in a yield of 50%-70%. Structures and purity were confirmed by GC/MS and NMR. 

Each substituted benzyl ether has a different oxidation potential (1.45 V for the DMB-OR, and 1.78 V for the PMB-OR), so each methoxy substitution pattern results in different rates of ether cleavage. This means that the DMB group can be removed in the presence of a PMB ether with high selectivity (eq 3). It has also been shown that other methoxybenzyl ethers react at widely differing rates. For example, the reaction time for the DMB ether was <20 min (86% yield of alcohol), and the 2,6-dimethoxy isomer required 27.5 h (80% yield) (eq 4). Other substitution patterns give reaction times between these two extremes. 

Acetattzation. Diethyl acetals are formed from carbonyl compounds by functional group exchange with triethyl orthoformate (EtOH also present) under the influence of DDD." Benzylic activation. Hydride abstraction by DDQ from benzyl ethers, where the benzylic position is also activated by a nuclear substitutent (e.g., methoxy group), prepares such compounds to be attacked by nucleophiles. The reaction constitutes an important step in a synthesis of deoxyfrenolicin. ... 

Quinodimethanes have been employed in a stereoselective synthesis (ref. 128) of estrone. A silicon-stabilised benzylic carbanion was obtained, avoiding lithiation of the methoxy-substituted ring, from the intermediate [2-[(trimethylsilyl)methyl]-5-methoxybenzyl]dimethylamine and after alkylation with the requisite cyclopentano component, generation of the quinodimethane structure with CsF afforded racemic estrone methyl ether. 

The reaction of 3,3-dichloro-2-methoxyazetidine 35 with lithium aluminium hydride in ether afforded 3-chloro-azetidine 36 (Equation 8). The substitution of the methoxy group by hydride via an azetinium intermediate and subsequent conversion of the geminal dichloro derivative to the monochloroazetidine via a single electron transfer reaction yielded this compound <1998JOC6>. Treatment of 1-benzyl-3-hydroxyazetidine 37 with triphenylphos-phine in carbon tetrachloride yielded l-benzyl-3-chloroazetidine 38 (Equation 9) <2004JOC2703>. 

Oxidations of l-(4-methoxyphenyl)-2-(4-substituted phenyl)ethanols, (6), [identical to alcohols (4a) to (4e) except for methylation of the 4-OH group] were also studied with cerium(IV) as the catalyst (Fisher, T. H., et al., J. Org. Chem., in press). To determine if oxidation occurs by electron abstraction from the benzylic hydroxyl or the aromatic ring, a competitive oxidation procedure was examined on the diaryl ethanol 6a and its methyl ether analog, 1-methoxy-l-(4-methoxyphenyl)-2-phenylethane, (7), (Fisher, T. H., et al., J. Org. Chem., in press). 

---