Sodium benzyl ethers

Prepare a solution of benzyl magnesium chloride in a 2-litre three-necked flask from 24-3 g. of magnesium turnings, 600 ml. of sodium-dried ether and 126-5 g. (115 ml.) of redistilled benzyl chloride follow the experimental details given under n-Propylbenzene (Section IV,7). Cool the flask in running water or in ice water. Place a solution of 456 g. of n-butyl-p-toluenesulphonate (Section IV,198) in about twice its volume of anhydrous ether in the dropping funnel, and add it slowly with stirring, at such a rate that the ether just boils a white solid soon forms. The addition is complete after about 2 hours. Pour the reaction product... 

Phenylacetic acid. Use 5 0 g. of magnesium, 25 g, (23 ml.) of redistilled benzyl chloride (Section IV,22) and 75 ml. of sodium-dried ether. Allow the reaction mixture to warm to 15° and then decompose it with dilute hydrochloric or sulphuric acid. Filter off the crude acid and recrystallize it from water. The yield of pure phenylacetic acid, m.p. 76-77°, is 11 g. 

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). 

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). 

Na, /-BuOH, 70-80°, 2 h, 78%. In this example sodium in /-butyl alcohol cleaves two aiyl benzyl ethers and reduces a double bond that is conjugated with an aromatic ring nonconjugated double bonds are stable. 

Benzyl ether [103-50-4] M 198.3, b 298°, 158-160 /0.1mm, d 1.043, n 1.54057. Refluxed over sodium, then distd under reduced pressure. Also purified by fractional freezing. 

Sodium A-methylanilide, xylene, HMPA, 60-120°, 70-95% yield. Methyl ethers of polyhydric phenols are cleaved to give the mono-phenol. Benzyl ethers are also cleaved. Halogenated phenols are not effectively cleaved, because of competing aromatic substitution. 

The thenyl chlorides appear to be more reactive in nucleophilic aliphatic substitution than the benzyl analogs. Thus, 2-thenyh chloride gives, in the reaction with sodium cyanide in ethanol, a mixture of ethyl 2-thenyl ether (25% yield) and 2-thenyl cyanide (32% yield), whereas benzyl chloride gives a high 3deld of benzyl cyanide uncontaminated with benzyl ether. When 2-thenyl chloride and benzyl chloride were allowed to compete for a deficiency of sodium amyloxide, 2-thenyl chloride reacted three times faster. In acetone solution 2-thenyl cyanide is obtained smoothl. ... 

In a further development on this theme, the thiol, 153, is first alkylated to the corresponding benzyl ether (158). Treatment with sodium methoxide removes the proton on the amide nitrogen to afford the ambient anion (159). This undergoes alkylation with methyl bromide on the ring nitrogen thus it locks amide into the imine form (160). Chlorolysis serves both to oxidize the sulfur to the sulfone stage and to cleave the benzyl ether linkage there is thus obtained the sulfonyl chloride, 161. 

You will note that the oxygen atoms attached to carbons 5 and 12 in 43 reside in proximity to the C-9 ketone carbonyl. Under sufficiently acidic conditions, it is conceivable that removal of the triethylsilyl protecting groups would be attended by a thermodynamically controlled spiroketalization reaction.30 Indeed, after hydro-genolysis of the C-26 benzyl ether in 43, subjection of the organic residue to the action of para-toluenesulfonic acid in a mixture of methylene chloride, ether, and water accomplishes the desired processes outlined above and provides monensin methyl ester. Finally, saponification of the methyl ester with aqueous sodium hydroxide in methanol furnishes the sodium salt of (+)-monensin [(+)-1], Still s elegant synthesis of monensin is now complete.13... 

The last reaction perhaps involves an intermediate such as 33a which expells a proton and dimethyl sulfide. Formation of the Schiff s base with t-butylamine, reduction with sodium borohydride and hydrogenolysis of the benzyl ether produces sulfonterol (28). Despite the fact that the methylene hydrogen of sulfonterol must be much less acidic than of the corresponding urea proton on carbuterol or the sulfonamide proton on soterenol, good bioactivity is retained. 

The diphenolic protoberberine methobromide 285 derived from 283 was refluxed in aqueous ethanolic sodium hydroxide for 12 hr to furnish the quinomethide 287 in 92% yield (Scheme 50). Compound 287 was treated with dimethyl sulfoxide to give rise to the desired diphenolic ochotensimine analog 288 through enolization (150,151). The presence of the phenolic hydroxyl group is essential in this rearrangement because the benzyl ether (284) was recovered unchanged under the same alkaline conditions. 

Ethyl Benzyl Ether [Brpnsted Acid Promoted Reduction of an Aldehyde to an Unsymmetrical Ether].327 To a cooled mixture of benzaldehyde (4.3 g, 41 mmol) and absolute ethanol (3.7 g, 80 mmol) was added trichloroacetic acid (18.2 g, 111 mmol). Et3SiH (6.96 g, 60 mmol) was then added dropwise with stirring while the mixture was maintained at 50-60°. After 4 hours, the reaction mixture was diluted with water, neutralized with aqueous NaHC03 solution, and extracted with Et20. The dried ether extract was distilled and the 170-190° fraction was collected. Distillation from sodium gave ethyl benzyl ether 4.8 g (90%) bp 187-189°. 

The causes of variations in yield by the use of the okler methods can now be explained. When benzaldehyde is added to the alcoholate, and especially when the latter is still warm, local overheating results in fact, the temperature may rise far above xoo° with the result that benzyl ether is formed. Simultaneously, the sodium benzylate is converted into sodium benzoate, which is of no value for inducing the desired reaction, and consequently very little benzyl benzoate is obtained. The same side reactions explain the failure of this experiment when the benzyl alcohol used in preparing the catalyst (sodium benzylate) is contaminated with benzaldehyde. 

The cleavage of benzyl ethers using hydrobromic acid is promoted by tetra-n-butylammonium bromide [38]. Selective cleavage of aryl silyl ethers can be effected in the presence of aliphatic silyl ethers using solid sodium hydroxide with tetra-n-butyl-ammonium hydrogen sulphate [39]. 

Cleavage of a benzyloxy bond was also accomplished by treatment with sodium in liquid ammonia [640] or by refluxing with sodium and butyl alcohol [641]. On the other hand, aluminum amalgams reduced a nitro group but did not cleave benzyl ether bond in dibenzylether of 2-nitrohydroquinone [642]. 

Aromatic Compounds.—A number of 2,3-dihydroxyoestra-l,3,5(10)-trienes have been prepared from the corresponding 2-amino-3-hydroxy-compounds using a novel inverse oxidation procedure followed by reduction with KI. Addition of the substrate to sodium metaperiodate in high dilution ensures no coupling with the intermediate quinonimines. 2-Bromo-oestradiol was readily converted into 2-methoxyoestradiol by treatment with NaOMe-MeOH-DMF-CuI. Novel preparations of the biologically interesting 11/3-methyl- and 11/3-ethyl-oestradiol have been reported in full. The key intermediates were the 11-oxo-oestradiol 3-benzyl ether (82) and its 9/3-epimer (83). The latter was derived from the 9,H-epoxides (81) by treatment with KOH followed by benzylation. The thermodynamically unstable 9a-epimer (82) was prepared from the 9j8-epimer (83) by... 

Azadienes of this sort were studied simultaneously by Mariano et al., who reacted mixtures of (1 ,3 ) and (1E, 3Z)-l-phenyl-2-aza-l,3-pentadiene 275 with several electron-rich alkenes, e.g., enamines and enol ethers (85JOC5678) (Scheme 61). They found the (l ,3 )-stereoisomer to be reactive in this process affording stereoselectively endo 276 or exo 277 piperidine cycloadducts in 5-39% yield, after reductive work-up with sodium borohydride. The stereochemistry of the resulting adducts is in agreement with an endo transition state in the case of dienophiles lacking a cis alkyl substituent at the /8-carbon (n-butyl vinyl ether, benzyl vinyl ether, and 1-morpholino cyclopentene), whereas an exo transition state was involved when dihydropyrane or c/s-propenyl benzyl ether were used. Finally, the authors reported that cyclohexene and dimethyl acetylenedi-carboxylate failed to react with these unactivated 2-azadienes. 

Most of the early syntheses of psilocin and psilocybin employ the O-benzyl ether as a protecting group. This provides more stability to the chemical intermediates, but also requires the additional step of reductive debenzylation. The flow chart of this process is conversion of 4-hydroxyindole to 4-benzyloxyindole via the sodium salt, with benzyl chloride the conversion of this with oxalyl chloride to 4-benzyloxyindole-3-glyoxylchloride the conversion of this to 4-benzyloxy-3-(N,N-dimethyl-glyoxamide with anhydrous dimethylamine the conversion of this to... 

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