Hydrogenolysis of benzyl ethers

The disadvantages of the general method using supported palladium and hydrogen are a lack of selectivity and overreduction. Where selectivity is not an important requirement, Pd/C is a widely used catalyst for the hydrogenolysis of the C-O bond in benzyl ethers. 

Examples In a typical experiment, a benzyl ether in absolute methanol was added to a tube containing Pd/C and a stir bar. Three drops of concentrated HCl were added and the mixture was stirred under a gentle flow of hydrogen for 5 minutes. The tube was sealed and pressurized with hydrogen (40 psi) and stirring was continued for 6 hours. During these circumstances, the benzyl group was completely removed.65 

Boc-O-benzyl-L-homoserine (Boc = t-butoxicarbonyl) was transformed to L-proline methyl ester, and the benzyl ether was removed by hydrogenolysis. The compound was dissolved in 50% acetic acid in methanol and the reaction mixture was degassed by bubbling nitrogen for 5 minutes then 10% Pd/C was added. The system was evacuated for 5 minutes and then pressured to 45 psi of hydrogen for 48 hours at room temperature.66 

During the synthesis of tellimagrandin, debenzylation was accomplished over 10% Pd/C in dry THE The mixture was purged six times with hydrogen and stirred at room temperature under 1 atm of hydrogen for 48 hours and finally purged with argon.67 

Deprotection of a primary benzyl ether was carried out by hydrogenolysis over 10% Pd/C in ethanol. Hydrogenolysis of its acetate derivative in polar-protic solvents like ethanol gave a 61% yield of the undesired product result- 

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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. 

AUylic ethers were reduced by treatment with lithium in ethylamine to alkenes [636]. Benzyl ethers are hydrogenolyzed easily, even more readily than benzyl alcohols [637], 3,5-Bis(benzyloxy)benzyl alcohol gave 3,5-dihydroxy-benzyl alcohol on hydrogenation over palladium on carbon at room temperature and atmospheric pressure in quantitative yield [638. Hydrogenolysis of benzylic ethers can also be achieved by refluxing the ether with cyclohexene (as a source of hydrogen) in the presence of 10% palladium on carbon in the presence of aluminum chloride [639]. 

Protection of hydroxyl groups (11, 166).- 3.4-Dimethoxybcnzyl ethers are oxidized by DDQ more readily thanp-methoxybenzyl ethers. Moreover, the dimethoxybenzyl ethers of secondary alcohols can be selectively oxidized in the presence of the corresponding ethers of primary alcohols. Benzyl, p-methoxybenzyl, and 3,4-dimethoxybenzyl ethers all undergo hydrogenolysis catalyzed by Pt/C or Pd/C, but selective hydrogenolysis of benzyl ethers is possible with W-2 Raney Ni. 

Suitably protected spiro isoxazoline 129 afforded the amino alcohol 130 with concomitant hydrogenolysis of benzyl ethers and reductive cleavage of the N-O bond by hydrogenation over Pd(OH)2/C (Equation 14) <2006TL6143>. 

Imines can be saturated in preference to the hydrogenation of aldehydes, ketones or nitriles and the hydrogenolysis of benzyl ethers and amines. Alkenes, alkynes and nitro groups are, however, usually hydrogenated in preference to an imine. 

Both catalytic and chemical methods are effective for the hydrogenolysis of benzyl ethers. Catalytic methods have found much wider use than the chemical methods, presumably because of the milder conditions that prevail. A general survey of the hydrogenolysis of benzyl compounds (benzyl amines, sulfides, and esters are also subject to hydrogenolysis to varying degrees) has recently been made, and the reader is referred to this discussion for a complete treatment of the scope of the reaction. 

Palladium is the favored catalyst, although Raney nickel has been found satisfactory for the hydrogenolysis of benzyl ethers of sugars. Copper chromite has been successfully employed in other systems. ... 

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. 

Heterogeneous hydrogenation, especially with palladium catalysis, is not normally selective and, in addition to hydrogenation of alkenes, hydrogenolysis of benzyl ethers occurs readily (although aromatic heterocycles are not normally reduced under these conditions). Therefore in this case the product is as shown below ... 

Although hydrogenolysis of benzyl ethers is slower than benzyloxycarbonyl derivatives, especially when an amine is used as an additive, "" they are still readily reduced in a variety of solvents (Scheme 80). "" "" ... 

In a competitive hydrogenolysis reaction between 0-benzyl ether and Af-benzylamine groups, the latter was preferably hydrogenolyzed. Amines have been shown to have an inhibitory effect on the hydrogenolysis of benzyl ether. ... 

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