Ethers benzylic, hydrogenolysis

The acid 350 was demethylated with pyridine hydrochloride, then realkylated with benzyl bromide in aqueous potassium hydroxide to give 351. The latter was converted to the diazoketone 352 by the sequential treatment of 351 with oxalyl chloride and etheral diazomethane. Reaction of 352 with concentrated hydrobromic acid gave the bromoketone 353. The latter was reduced with sodium borohydride at pH 8 -9 to yield a mixture of diastere-omeric bromohydrins 354. Protection of the free hydroxyl as a tetrahydro-pyranyl ether and hydrogenolysis of the benzyl residue afforded 355. The phenol 355 was heated under reflux with potassium m/V-butoxide in tert-butyl alcohol for 5 hr to give a 3 1 epimeric mixture of dienone ethers 356 and 357 in about 50% yield. Treatment of this mixture with dilute acid gave the epimeric alcohols 358 and 359. This mixture was oxidized with Jones reagent to afford the diketone 349. 

Ethers may be removed commonly by acid, with the THE derivative 1.79 reacting more rapidly than the tert-hutyl ether. Benzyl ethers may be removed under a variety of conditions such as hydrogenolysis, dissolving metal reduction (Na in NH3) and HBr (mild). Methyl ethers are cleaved by refluxing with EtSNa and DME tert-Butyl ethers can be cleaved with trifluroacetic acid (CE3COOH) at 25°C. 

The benzyloxycarbonyl group (Cbz or Z) is useful in carbohydrate syuithesis, not only for IV-protection of amino sugars, but also to protect alcohols [262,263]. The main advantage of this group is that it is cleaved by hydrogenolysis, and when compared to benzyl ethers, benzyl carbonates are not only removed more readily [264] but also allow hydroxyl group protection under softer conditions than those employed for benzylation. 

Hydrogenolysis of benzyl ethers is accelerated by a titanium-loaded hexagonal mesoporous silica without affecting silyl ethers and acetals. 2-Naphthylmethyl ethers undergo hydrogenolysis in the presence of benzyl ethers under standard conditions. 2-Methylnaphthalene inhibits hydrogenolysis of benzyl ethers. 

Among ethers, benzylic ethers are unique in that they are cleaved under the conditions of catalytic hydrogenation as illustrated by the hydrogenolysis of benzyl hexyl ether. In this illustration, the benzyl group is converted to toluene, and the alkyl group is converted to an alcohol. 

In our efforts, we found that ethers other than methyl transfer efficiently as long as steric or electronic differences were insignificant. In fact, benzyloxymethyl substrates 57, readily prepared from protection of homoallylic alcohols with commercially available BOMCl, underwent efficient benzyl ether transfer (Scheme 37.16). This process significantly expands the scope of the reaction because, in contrast to methyl ethers, benzyl groups can be easily cleaved by hydrogenolysis. Thus, the ether transfer can provide access to orthogonally protected iy -l,3-diol units. 

Historically, simple Vz-alkyl ethers formed from a phenol and a halide or sulfate were cleaved under rather drastic conditions (e.g., refluxing HBr). New ether protective groups have been developed that are removed under much milder conditions (e.g., via nucleophilic displacement, hydrogenolysis of benzyl ethers, and mild acid hydrolysis of acetal-type ethers) that seldom affect other functional groups in a molecule. 

The 2,6-dimethylbenzyl ether is considerably more stable to hydrogenolysis than is the benzyl ether. It has a half-life of 15 h at 1 atm of hydrogen in the presence of Pd-C whereas the benzyl ether has a half-life of —45 min. This added stability allows hydrogenation of azides, nitro groups, and olefins in the presence of a di-methylbenzyl group. ... 

The 4-(dimethylaminocarbonyl)benzyl ether has been used to protect the phenolic hydroxyl of tyrosine. It is stable to CF3CO2H (120 h), but not to HBr/AcOH (complete cleavage in 16 h). It can also be cleaved by hydrogenolysis (H2/Pd-C). ... 

Esters and amides are quite resistant to hydrogenation under almost all conditions so their presence is not expected to cause difficulties. Alkyl ethers and ketals are generally resistant to hydrogenolysis but benzyl ethers are readily cleaved, particularly over palladium or Raney nickel catalysts. ... 

Catalytic hydrogenolysis of an O-benzyl protective group is a mild, selective method introduced by Bergmann and Zervas to cleave a benzyl carbamate (>NC0-0CH2C6H5 —> >NH) prepared to protect an amino group during peptide syntheses. The method has also been used to cleave alkyl benzyl ethers, stable compounds prepared to protect alkyl alcohols benzyl esters are cleaved by catalytic hydrogenolysis under neutral conditions. 

Pd/C, H2, EtOAc, >52% yield. The p-phenylbenzyl ether is more easily cleaved by hydrogenolysis than are normal benzyl ethers. This property was used to great advantage in the deprotection of the following vineo-mycinone intermediate ... 

PdO, cyclohexene, methanol, 30 min for a primary ROH, 90-95% yield. Secondary alcohols require longer times. The primary TBDPS and TIPS groups are cleaved much more slowly (18-21 h). Benzylic TBDMS ethers are cleaved without hydrogenolysis. ... 

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