6-benzyl ether

Benzyl ethers of carbohydrates are formed with both primary and secondary hydroxyl groups by reaction with benzyl chloride or bromide in a strong alkaline solution of the carbohydrate. The carbohydrate is dissolved directly in the benzyl halide, containing 4.5 M potassium hydroxide, and heated to 90-100 C for several hours [13] (reaction 4.17). Sometimes the carbohydrate is dissolved in dioxane or dimethylformamide (DMF), containing 4.5 M potassium hydroxide and benzyl halide, and heated for several hours. Difficult benzylations are accomplished by dissolving the carbohydrate in DMF that was treated with sodium hydride, similar to the Hakomori reagent, followed by the addition of benzyl halide [14]. 

The benzyl groups can be removed by catalytic hydrogenolysis, using Pd/C catalyst [16]. A very simple, specific, and mild alternative method of removal uses ferric chloride in methylene chloride for 15-30 min at 20°C, and results in 70% yields [17]. Methyl ethers and esters are not removed by this procedure. 

In carbohydrate chemistry, benzyl ethers are often applied as permanent protecting groups. They are robust and are stable to a wide range of basic and acidic conditions. They can also withstand hydride reducing agents 

Cyclic dibutylstannylene derivatives are convenient intermediates for the regioselective benzylation of polyols.6 These derivatives can easily be prepared by reaction with Bu2SnO or Bu2Sn(OMe)2 with removal of water or methanol, respectively. They can be alkylated in benzene, 

Catalytic hydrogenolysis using Pd—C, Pd(OH)2 or Pd(OAc)2 is the most commonly employed method for the removal of benzyl ethers, and yields are often quantitative. Cyclohexene, cyclohexadiene, formic acid and ammonium formate can also be used as hydrogen sources rather than hydrogen. Benzyl ethers can also be removed by Birch reduction with lithium or sodium dissolved in liquid ammonia, but this procedure is not often applied in carbohydrate chemistry. 

C(6) to give an oxonium ion. Nucleophilic attack, probably by acdtic acid, on the benzylic carbon gives a O-acetyl sugar derivative and benzyl acetate. Glycosides are also acetolysed under these reaction conditions. 

C(2) and C(4). As a result different regioselectivities are observed when 0-benzylated 1,6-anhydro glucose or mannose derivatives are treated with Lewis acids. 

The use of stannylene acetals and stannyl ethers is widely used for achieving selective benzylation, the selectivity paralleling that observed for allylation (see section 2.3.2, AUyl ethers). 

6-anhydroglucose analogues, which lack the required disposition of oxygens, fail to react with useful selectivity. 

A great attraction of benzyl as a protecting group core is its ability to be tuned both sterically and electronically which leads to a degree of graduated lability within 

In terms of electronic tuning, it has been mentioned already that electron-donating phenyl substituents confer increased lability towards oxidizing agents, and para-methoxybenzyl (PMB) ethers—introduced by methods analogous to those used for the benzyl group—are routinely employed because they can be removed highly 

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Six protective groups for alcohols, which may be removed successively and selectively, have been listed by E.J. Corey (1972B). A hypothetical hexahydroxy compound with hydroxy groups 1 to 6 protected as (1) acetate, (2) 2,2,2-trichloroethyl carbonate, (3) benzyl ether, (4) dimethyl-t-butylsilyl ether, (5) 2-tetrahydropyranyl ether, and (6) methyl ether may be unmasked in that order by the reagents (1) KjCO, or NH, in CHjOH, (2) Zn in CHjOH or AcOH, (3) over Pd, (4) F", (5) wet acetic acid, and (6) BBrj. The groups may also be exposed to the same reagents in the order A 5, 2, 1, 3, 6. The (4-methoxyphenyl)methyl group (=MPM = p-methoxybenzyl, PMB) can be oxidized to a benzaldehyde derivative and thereby be removed at room temperature under neutral conditions (Y- Oikawa, 1982 R. Johansson, 1984 T. Fukuyama, 1985). 

The benzyl group has been widely used for the protection of hydroxyl functions in carbohydrate and nucleotide chemistry (C.M. McCloskey, 1957 C.B. Reese, 1965 B.E. Griffin, 1966). A common benzylation procedure involves heating with neat benzyl chloride and strong bases. A milder procedure is the reaction in DMF solution at room temperatiue with the aid of silver oxide (E. Reinefeld, 1971). Benzyl ethers are not affected by hydroxides and are stable towards oxidants (e.g. periodate, lead tetraacetate), LiAIH, amd weak acids. They are, however, readily cleaved in neutral solution at room temperature by palladium-catalyzed bydrogenolysis (S. Tejima, 1963) or by sodium in liquid ammonia or alcohols (E.J. Rcist, 1964). 

Debenzylation of benzylamines and benzyl ethers is carried out with ammonium formate[l 13,l 14]. Hydrosilanes are also used for debenzylation[l I5. ... 

Photo grade contains 0.01—0.02% of a hydroquinone monomethyl or benzyl ether to prevent the oxidation of the alcohol to benzaldehyde. 

Reactions of the Side Chain. Benzyl chloride is hydrolyzed slowly by boiling water and more rapidly at elevated temperature and pressure in the presence of alkaHes (11). Reaction with aqueous sodium cyanide, preferably in the presence of a quaternary ammonium chloride, produces phenylacetonitrile [140-29-4] in high yield (12). The presence of a lower molecular-weight alcohol gives faster rates and higher yields. In the presence of suitable catalysts benzyl chloride reacts with carbon monoxide to produce phenylacetic acid [103-82-2] (13—15). With different catalyst systems in the presence of calcium hydroxide, double carbonylation to phenylpymvic acid [156-06-9] occurs (16). Benzyl esters are formed by heating benzyl chloride with the sodium salts of acids benzyl ethers by reaction with sodium alkoxides. The ease of ether formation is improved by the use of phase-transfer catalysts (17) (see Catalysis, phase-thansfer). 

Irradiation of 1,2,3-triphenylaziridine (98) in various alcohols has been reported to give benzaldehyde acetals and N-benzylaniline (68T2193). Competitive fragmentation to give N-(benzylidene)aniline and phenylcarbene, which is trapped as the alkyl benzyl ether, also appears to occur. 

Me3SiBr, CH2CI2, 0°, 8-9 h, 80-97% yield.This reagent also cleaves the acetonide, THP, trityl, and r-BuMe2Si groups. Esters, methyl and benzyl ethers, r-butyldiphenylsilyl ethers, and amides are reported to be stable. 

NBS, CH3CN, H2O, 62-90% yield.The POM group has been selectively removed in the presence of an ethoxy ethyl ether, TBDMS ether, benzyl ether, p-methoxybenzyl ether, an acetate, and an allyl ether. Because the hydrolysis of a pentenyl 2-acetoxyglycoside was so much slower than a pentenyl 2-benzyloxyglycoside, the 2-benzyl derivative could be cleaved selectively in the presence of the 2-acetoxy derivative. The POM group is stable to 75% AcOH, but is cleaved by 5% HCl. 

Me3SiCl, Nal, CH3CN, —20°, 79%. Allylic and benzylic ethers tend to form some iodide as a byproduct, but less iodide is formed than when Me3SiI is used directly. 

Lithium aluminum hydride will also cleave benzyl ethers, but this is seldom practical because of its high reactivity to other functional groups. ... 

C1O3/ACOH, 25°, 50% yield, [- ROCOPh (- ROH + PhC02H)]. This method was used to remove benzyl ethers from carbohydrates that contain functional groups sensitive to catalytic hydiogenation or dissolving metals. Esters are stable, but glycosides or acetals are cleaved. 

BuMgBr, benzene, 80°, 69%. MeMgl fails in this reaction. In general, benzyl ethers are quite stable to Grignard reagents because these reactions are rarely run at such high temperatures. 

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). ... 

The section on the formation of benzyl ethers should also be consulted. 

Electrolytic oxidation Ar3N, CH3CN, LiC104, 20 , 1.4-1.7 V, 80-90% yield. Benzyl ethers are not affected by these conditions. 

Dichlorodicyanoquinone (DDQ), CH2CI2, H2O, 40 min, it, 84-93% yield.This method does not cleave simple benzyl ethers. This method was found effective in the presence of a boronate. The following groups are stable to these conditions ketones, epoxides, alkenes, acetonides, to-sylates, MOM ethers, THP ethers, acetates, benzyloxymethyl (BOM) ethers, and TBDMS ethers. 

The o-nitrobenzyl and p-nitrobenzyl ethers can b prepared and cleaved by many of the methods described for benzyl ethers. The p-nitrobenzyl ether is also prepared from an alcohol and p-nitrobenzyl alcohol (trifluoroacetic anhydride, 2,6-lutidine, CH2CI2, 67% yield). In addition, the o-nitrobenzyl ether can be cleaved by irradiation (320 nm, 10 min, quant, yield of carbohydrate " 280 nm, 95% yield of nucleotide ). The p-nitrobenzyl ether has been cleaved by electrolytic reduction (—1.1 V, DMF, R4N X, 60% yield) and by reduction with Na2S204 (pH 8-9, 80-95% yield). These ethers can also be cleaved oxidatively (DDQ or electrolysis) after reduction to the aniline derivative. ... 

FeCl3, CH2CI2, 2-3 min, 68% yield. Benzyl ethers are cleaved in 15-20 min under these conditions. Methyl glycosides, acetates and benzoates were not affected by this reagent. 

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. 

Mel, K2CO3, acetone, reflux, 6 h. This is a veiy common and often veiy efficient method for the preparation of phenolic methyl ethers it is also applicable to the. formation of phenolic benzyl ethers. 

Methyl, ethyl, and benzyl ethers have been prepared in the presence of tetraethylammonium fluoride as a Lewis base (alkyl halide, DME, 20°, 3 h, 60-85% yields). ... 

Phenols protected as r-BuMe2Si ethers can be converted directly to methyl or benzyl ethers (Mel or BnBr, KF, DMF, rt, >90% yield). ... 

Lithium diphenyphosphide (THF, 25°, 2 h HCl, H2O, 87% yield) selectively cleaves an aryl methyl ether in the presence of an ethyl ether.It also cleaves a phenyl benzyl ether and a phenyl allyl ether to phenol in 88% and 78% yield, respectively. ... 

Bromo-l,3,2-benzodioxaborole, CH2CI2 (cat. BF3 Et20), 25°, 0.5-36 h, 95-98% yield. Aryl benzyl ethers, methyl esters, and aromatic benzoates are also cleaved. ... 

NaAlH2(0CH2CH20CH3)2, PhCH3, reflux, 10 h, 62% yield/ An aryl allyl ether is selectively cleaved by this reagent (which also cleaves aryl benzyl ethers) in the presence of an A-allylamide. 

An isopropyl ether was developed as a phenol protective group that would be more stable to Lewis acids than an aryl benzyl ether. The isopropyl group has also been... 

In general, benzyl ethers are prepared from a phenol by treating an alkaline solution of the phenol with a benzyl halide. ... 

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