Benzyl Alcohols, Ethers and Esters

The breaking of the benzyl-oxygen bond of benzyl alcohols, ethers and esters takes place most easily over a palladium catalyst at room temperature and atmospheric pressure.36 BenzhydryP and trityP compounds are also 

Ring hydrogenation occurs in preference to hydrogenolysis over ruthenium, rhodium, platinized Raney nickel and platinum oxide in the presence of a trace of acetic acid.42-45 the latter system, the extent of ring 

Aryl benzyl ethers are cleaved more easily than are alkyl benzyl ethers. The presence of an amine hinders the hydrogenolysis of alkyl benzyl ethers but has no effect on the cleavage of aryl benzyl ethers. - Because of this the benzyl ether is selectively hydrogenolyzed in compounds containing both a benzyl amine and an aryl benzyl ether (Eqn. 20.24)55 but the benzyl amine is selectively cleaved in compounds having both a benzyl amine and an alkyl benzyl ether (Eqn. 20.25).53,54,56 

The hydrogenolysis of benzyl esters provides a means for the selective eonversion of the ester to the acid under mild conditions. Substituted dibenzyl malonates are easily converted to the substituted malonic acids by hydrogenolysis in neutral medium thus avoiding the acyl cleavage or decarboxylation which can result from base or acid catalyzed ester hydrolysis (Eqns. 20.26-27).5 . 58 Monobenzylmalonates are selectively debenzylated and decarboxylated to give the substituted acetic esters. 

The hydrogenolysis of benzyl protecting groups on poly(benzyl acrylates) and related polymers was successfully accomplished over Pd/C at room temperature and atmospheric pressure provided the palladium was present on the surface of the support and not in the pores.59 

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Similar utilization for cleavage of benzyl alcohols, ethers and esters has made this method the preferred one where regioselectivity is required, but for allylic cleavage double bond isomerization becomes a problem. A number of benzylic ethers and alcohols (equation 13), and benzhydric ethers and acetals (equation 14) have been cleaved in relatively high yield using cyclohexene in the presence of AlCb. Mild conditions of cleavage are frequently required for debenzylation of carbohydrates and a number of protected carbohydrates have been cleaved with formic acid as donor (equation 15). ... 

The oxygen nucleophiles that are of primary interest in synthesis are the hydroxide ion (or water), alkoxide ions, and carboxylate anions, which lead, respectively, to alcohols, ethers, and esters. Since each of these nucleophiles can also act as a base, reaction conditions are selected to favor substitution over elimination. Usually, a given alcohol is more easily obtained than the corresponding halide so the halide-to-alcohol transformation is not used extensively for synthesis. The hydrolysis of benzyl halides to the corresponding alcohols proceeds in good yield. This can be a useful synthetic transformation because benzyl halides are available either by side chain halogenation or by the chloromethylation reaction (Section 11.1.3). 

Thus, with halides, alcohols, ethers, and esters, alkylation proceeds most readily for tertiary or benzyl types, less readily for secondary types, still less readily for primary types, and least readily for methyl. It is therefore generally necessary to use increasin y vigorous catalysts or conditions to introduce the alkyl groups in the above sequence. For example, reactive halides like benzyl chloride will react with benzene in the presence of traces of such a weak catalyst as zinc chloride, whereas an inert halide like methyl chloride requires a considerable quantity of a powerful catalyst such as aluminum chloride. 

Hydrogenolysis is not possible for ordinary alcohols, ethers, and esters. Therefore, the phenylmethyl (benzyl) substituent is a valuable protecting group for hydroxy functions. The following scheme shows its use in part of a synthesis of a compound in the eudesmane class of volatile plant oils, which includes substances of importance in both medicine and perfumery. 

Me3SiI, CH2CI2, 25°, 15 min, 85-95% yield.Under these cleavage conditions i,3-dithiolanes, alkyl and trimethylsilyl enol ethers, and enol acetates are stable. 1,3-Dioxolanes give complex mixtures. Alcohols, epoxides, trityl, r-butyl, and benzyl ethers and esters are reactive. Most other ethers and esters, amines, amides, ketones, olefins, acetylenes, and halides are expected to be stable. 

As expected, other enol ethers work well in these procedures. For example, Jones and Selenski find that implementation of method F, which occurs by addition of MeMgBr to benzaldehyde 5 in the presence of dihydropyran (DHP) at 78 °C affords a 66% yield of the corresponding tricyclic ketal 59 with better than 50 1 endo diastereoselectivity (Fig. 4.31).27 On the contrary, Lindsey reports use of method H with the benzyl alcohol 35 and diethylketene acetal. The cycloaddition reaction occurs almost instantaneously upon deprotonation of the benzyl alcohol 35 by f-butyl-magnesium bromide in the presence of the ketene acetal and yields the corresponding benzopyran ortho ester 60 in a 67% yield.29... 

Sodium or lithium in liquid ammonia cleave benzylic ethers and esters in the presence of a proton source to provide a pentadienyl anion which expels an alkoxide or carboxylate leaving group [Scheme 1.15]. Aqueous acidic workup returns the carboxylic acid or alcohol and toluene. Many functional groups are unable to survive such powerful reducing conditions. 

The typical reactions of the alcohol group include their conversion to ethers and esters by reaction with alkyl halides and with acid chlorides or anhydrides, respectively (Scheme 6.2). The benzyl ether group is readily cleaved by hydrogenolysis and is often used as a protecting group for alcohols. Primary alcohols are oxidized initially to the aldehyde and then to the carboxylic acid. 

The ether and ester derivatives of benzyl alcohols are widely utilized as protecting groups. In the case of protected peptides hydrogenolysis often has advantages over hydrolysis. This conversion is use-... 

Copper chromite (CuCr204) has historically been widely used as a hydrogenation catalyst. Generally because of its low catalytic activity its chemoselectivity is useful, although it does require high temperature and autoclave pressure conditions. It is effective for cleavage of benzylic alcohols, primary and secondary benzylic esters and ethers. Efficient cleavage of benzylamines has also been utilized (equation 29). Other copper salts and copper alloys have found infrequent use. 

These mutagenic studies showed that lucidin can be metabolised to a reactive compound which forms covalent adducts with DNA and possibly other macromolecules. It was reported that lucidin forms ethers and esters upon heating with alcohol or acids. This supports the reactive character of lucidin [57,97,153]. Kawasaki et al. (1994) proved that lucidin forms adducts with the nucleic acids adenine and guanine under physiological conditions [159]. These adducts were identified as condensed reactants at the benzylic position of lucidin with a nitrogen atom of a purine base. This... 

Reductive cleavage is facilitated when the anions are stabiUzed by resonance or by an electronegative atom. As expected, therefore, bonds between heteroatoms or between a heteroatom and an unsaturated system which can stabilize a negative charge by resonance, are particularly easily cleaved. Thus allyl and benzyl ethers and esters (and sometimes even allyl or benzyl alcohols) are readily cleaved by metal-amine systems (or by catalytic hydrogenation). This type of reaction has... 

Oxidation of Alcohols, Aldehydes, and Esters. Nitric acid oxidizes alcohols and aldehydes to the corresponding carboxylic acids. For example, l-chloro-3-propanol is oxidized to 3-chloropropanoic acid in 78-79% yield. 3-Chloropropional-dehyde affords the same product. Primary alcohols protected as esters are oxidized to the carboxylic acids (eq 11). In a two-phase solvent system (for example dimethyl ether and water), the oxidation of benzyl alcohols can be controlled so that aldehydes are obtained. ... 

Almost insoluble in cold water. Higher alcohols (including benzyl alcohol), higher phenols (e.g., naphthols), metaformaldehyde, paraldehyde, aromatic aldehydes, higher ketones (including acetophenone), aromatic acids, most esters, ethers, oxamide and domatic amides, sulphonamides, aromatic imides, aromatic nitriles, aromatic acid anhydrides, aromatic acid chlorides, sulphonyl chlorides, starch, aromatic amines, anilides, tyrosine, cystine, nitrocompounds, uric acid, halogeno-hydrocarbons, hydrocarbons. 

A one-pot conversion of benzyl alcohols to benzyl fluorides by treatment of the alcohols with a combination of methanesulfonyl fluoride, cesium fluoride and 18-crown 6 ether in tetrahydrofuran has been repotted The reaction involves mesylation of the alcohols followed by cleavage of the resultant mesyl esters with a fluoride ion The reaction has been extended also to certain heterocycles bearing the N hydroxymethyl group [43] (equation 31)... 

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