Benzyl ethers preparation

Cleavage conditions for alkyl benzyl ethers prepared from acid-labile benzyl alcohols are similar to those for the corresponding benzyl esters (Table 3.30). Aryl benzyl ethers, however, are generally cleaved more easily by acidolysis than esters or alkyl ethers. Phenols etherified with hydroxymethyl polystyrene, for instance, can even be released by treatment with TFA (Entry 1, Table 3.31). It has also been shown that Wang resin derived phenyl ethers are less stable than Wang resin derived esters towards refluxing acetic acid [29]. Alternatively, boron tribromide may be used to cleave aryl ethers from hydroxymethyl polystyrene [573],... 

The lithiated benzylic ether prepared from 79 is a carbon nucleophile. Under boron trifluoride catalysis10 it attacks diepoxide 6. In the process, the alkyl lithium reagent adds in a stepwise fashion to diepoxide 6, whereby the first addition is significantly more rapid than the second.7 One thus obtains only the monoadduct 24... 

Obviously, it is very desirable to substitute these modes of benzylic ether preparation by an heterogeneous catalysis process. Clays (50) and resins (51, 52) which were the first solid acid catalysts used have given low or moderate yields. The first experiments with zeolites were carried out by Rhodia (53, 54) on the etherification of vanillic alcohol (A) in a batch reactor over a HBEA zeolite with a Si/Al ratio of 12.5 ... 

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 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. ... 

The p-cyanobenzyl ether, prepared from an alcohol and the benzyl bromide in the presence of sodium, hydride (74% yield), can be cleaved by electrolytic reduction (—2.1 V, 71% yield). It is stable to electrolytic removal ( — 1.4 V) of a tritylone ether [i.e., 9-(9-phenyl-10-oxo)anthiyl ether]. ... 

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). ... 

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

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. 

The o nitrobenzyl and /7 nitrobenzyl ethers can be prepared and cleaved by many of the methods described for benzyl ethers. The p-nitrobenzyl ether is also... 

Benzyl ethers of phenols can also be prepared by reaction with phenyldi-azomethane. 

The synthesis of the trisubstituted cyclohexane sector 160 commences with the preparation of optically active (/ )-2-cyclohexen-l-ol (199) (see Scheme 49). To accomplish this objective, the decision was made to utilize the powerful catalytic asymmetric reduction process developed by Corey and his colleagues at Harvard.83 Treatment of 2-bromocyclohexenone (196) with BH3 SMe2 in the presence of 5 mol % of oxazaborolidine 197 provides enantiomeri-cally enriched allylic alcohol 198 (99% yield, 96% ee). Reductive cleavage of the C-Br bond in 198 with lithium metal in terf-butyl alcohol and THF then provides optically active (/ )-2-cyclo-hexen-l-ol (199). When the latter substance is treated with wCPBA, a hydroxyl-directed Henbest epoxidation84 takes place to give an epoxy alcohol which can subsequently be protected in the form of a benzyl ether (see 175) under standard conditions. 

The outcomes of intramolecular cyclizations of hydroxy vinylepoxides in more complicated systems can be difficult to predict. In a study of the synthesis of the JKLM ring fragment of dguatoxin, epoxide 44 was prepared and subjected to acid-mediated cydization conditions (Scheme 9.24) [114]. Somewhat surprisingly, the expected oxepane 45 was not formed, but instead a mixture of tetrahydropyran 46 and tetrahydrofuran 47 was obtained, both compounds products of attack of the C6 and C5 benzyl ether oxygens, respectively, on the allylic oxirane position (C3). Repetition of the reaction with dimsylpotassium gave a low yield of the desired 45 along with considerable amounts of tetrahydropyran 48. 

Palladium-catalyzed aminations of aryl halides is now a well-documented process [86-88], Heo et al. showed that amino-substituted 2-pyridones 54 and 55 can be prepared in a two-step procedure via a microwave-assisted Buchwald-Hartwig amination reaction of 5- or 6-bromo-2-benzyloxypyri-dines 50 and 51 followed by a hydrogenolysis of the benzyl ether 52 and 53, as outlined in Fig. 9 [89]. The actual microwave-assisted Buchwald-Hartwig coupling was not performed directly at the 2-pyridone scaffold, but instead at the intermediate pyridine. Initially, the reaction was performed at 150 °C for 10 min with Pd2(dba)3 as the palladium source, which provided both the desired amino-pyridines (65% yield) as well as the debrominated pyridine. After improving the conditions, the best temperature and time to use proved... 

As a strategy for the construction of cyclic ethers, the radical cyclization of jS-alkoxyacrylates was used for the preparation of czs-2,5-disubstituted tetrahy-drofurans and cis-2,6-disubstituted tetrahydropyrans. An example is given with S-alkoxymethacrylate 38 as precursor of the optically active benzyl ether of (+)-methyl nonactate, exclusively formed as the threo product (Reaction 44). ° ... 

The asymmetric reduction of the benzoxathiin is very appealing because of its simplicity (Scheme 5.3). It was envisioned that intermediate 16 could be prepared from thiol-phenol 7 and bro moke tone 17. Scheme 5.8 summarized the synthesis for 16. The l,3-benzoxathiol-2-one 35 was prepared from 1,4-benzoquinone and thiourea following a literature procedure with minor modifications. Benzylation of 35 with benzyl bromide in the presence of KI gave benzyl ether 36 as a crystalline solid. It was observed that the benzylation gave better results when the reaction was run under anaerobic conditions. Hydrolysis of thiocarbonate 36 gave free thiophenol 7 which was used directly in the next reaction. 

Arguably the most challenging aspect for the preparation of 1 was construction of the unsymmetrically substituted sec-sec chiral bis(trifluoromethyl)benzylic ether functionality with careful control of the relative and absolute stereochemistry [21], The original chemistry route to ether intermediate 18 involved an unselective etherification of chiral alcohol 10 with racemic imidate 17 and separation of a nearly 1 1 mixture of diastereomers, as shown in Scheme 7.3. Carbon-oxygen single bond forming reactions leading directly to chiral acyclic sec-sec ethers are particularly rare since known reactions are typically nonstereospecific. While notable exceptions have surfaced [22], each method provides ethers with particular substitution patterns which are not broadly applicable. 

The use of trichloroimidates for the preparation of ethers is an effective method for O-alkylation of alcohols [27]. This method has found widespread use in the protection of alcohols as benzyl ethers since the corresponding trichlorobenzylimi-date is inexpensive and commercially available. The mechanism involves activation of the imidate with a catalytic amount of a strong acid (typically TfOH) which leads to ionization of the electrophile and the formation of carbocation which is rapidly trapped by an alcohol. For the preparation of sec-sec ethers, this protocol has been limited to glycosidation reactions, due to the SN1 nature of the reaction which often leads to diastereomeric mixtures of products [26],... 

A large family of new dendrimers has been synthesized following this divergent method. Hawker and Frechet developed polyaryl(-benzyl)ether dendrimers [27], Miller andNeenan [28], and also Moore and Xu [29] prepared hydrocarbon dendrimers. The latter have reported the largest monodisperse organic hydrocarbon dendrimer with a molecular mass of 18 kDa and a diameter of 12.5 nm [30]. 

Dudley and co-workers have designed pyridinium triflate reagent 58 for the preparation of benzyl ethers <06JOC3923>. This reagent is easily prepared in two steps with good yield. Since it is also bench-stable and preactivated, the benzylation reaction occurs upon warming 58 in the presence of an alcohol with no need for acidic or basic promoters. 

Nevertheless, another possibility remained for the formation of insertion products, that they might be formed from the O-H insertion product, e.g., dichloromethyl benzyl ether 5, by the Wittig rearrangement of dichloromethoxy-carbanion 4, (Scheme 5, Eq. I).17 However, treatment of independently prepared benzyl dichloromethyl ether 5 with the same base solely gave benzyl chloride, but the insertion product was not obtained (Eq. 2). Hence, a Wittig-type rearrangement process was excluded. 

The reaction described is of considerable general utility for the preparation of benzoyloxy derivatives of unsaturated hydrocarbons.2"8 Reactions of 2-butyl perbenzoate with various other classes of compounds in the presence of catalytic amounts of copper ions produce benzoyloxy derivatives. Thus this reaction can also be used to effect one-step oxidation of saturated hydrocarbons,9, 10 esters,6,11 dialkyl and aryl alkyl ethers,12 14 benzylic ethers,11,15 cyclic ethers,13,16 straight-chain and benzylic sulfides,12, 17-19 cyclic sulfides,11,19 amides,11 and certain organo-silicon compounds.20... 

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