Acid-catalyzed benzylation

Step 2 The acid-catalyzed benzylation procedure prevents translactonization and/or substrate polymerization. 

Acid-Catalyzed Benzylation. Benzyl trichloroacetimidate, Cl3CC(=NH)OBn, reacts with hydroxyl groups under acid catalysis to give the con-esponding benzyl ethers in good yield. The method is particularly useful for the protection of base-sensitive substrates (i.e., alkoxide-sensitive), such as hydroxy esters or hydroxy lactones, as exemplified below. 

Using the acid-catalyzed benzylation of the ethyl lactate as described here avoids racemization during the reaction course and affords the product in high yield. In addition all reagents are commercially available and it is possible to carry out the reaction on a large scale. 

The benzyl analogue of the vinylogous Peterson reaction is called the benzo-Peterson reaction [374]. Reaction of the o-(hydroxymethyl)benzylsilane 218 with an excess of maleic anhydride in refluxing toluene yields the Diels-Alder cycloadduct 219 with endo selectivity (Scheme 2.139) [375, 376]. It is assumed that the reaction proceeds with formation of the benzyl cation 220, conversion to the o-quinodimethane 221 by the action of water, and cycloaddition of the latter with maleic anhydride in a stereoselective fashion. The initial steps are regarded as an acid-catalyzed benzyl analogue of the vinylogous Peterson reaction. It is noteworthy that the elimination of the silyl group is carried out under weakly acidic conditions. 

Finally a general approach to synthesize A -pyrrolines must be mentioned. This is tl acid-catalyzed (NH4CI or catalytic amounts of HBr) and thermally (150°C) induced tea rangement of cyclopropyl imines. These educts may be obtained from commercial cyan> acetate, cyclopropyl cyanide, or benzyl cyanide derivatives by the routes outlined below. Tl rearrangement is reminiscent of the rearrangement of 1-silyloxy-l-vinylcyclopropancs (p. 7 83) but since it is acid-catalyzed it occurs at much lower temperatures. A -Pyrrolines constitut reactive enamines and may be used in further addition reactions such as the Robinson anei lation with methyl vinyl ketone (R.V. Stevens, 1967, 1968, 1971). 

Substitution Reactions on Side Chains. Because the benzyl carbon is the most reactive site on the propanoid side chain, many substitution reactions occur at this position. Typically, substitution reactions occur by attack of a nucleophilic reagent on a benzyl carbon present in the form of a carbonium ion or a methine group in a quinonemethide stmeture. In a reversal of the ether cleavage reactions described, benzyl alcohols and ethers may be transformed to alkyl or aryl ethers by acid-catalyzed etherifications or transetherifications with alcohol or phenol. The conversion of a benzyl alcohol or ether to a sulfonic acid group is among the most important side chain modification reactions because it is essential to the solubilization of lignin in the sulfite pulping process (17). 

The cleavage proceeds by initial reduction of the nitro groups followed by acid-catalyzed cleavage. The DNB group can be cleaved in the presence of allyl, benzyl, tetrahydropyranyl, methoxy ethoxy methyl, methoxymethyl, silyl, trityl, and ketal protective groups. 

CF3OSO2F or CH3OSO2F, PhSCH3, CF3CO2H, 0°, 30 min, 100% yield. Thioanisole suppresses acid-catalyzed rearrangement of the benzyl group to form 3-benzyltyrosine. The more acid-stable 2,6-dichlorobenzyl ether is cleaved in a similar manner. 

An 6>-nitrobenzyl ether.can be cleaved by photolysis. In tyrosine this avoids the use of acid-catalyzed cleavage and the attendant conversion to S-beirayltyrosine. (Note that this unwanted conversion can also be suppressed by the addition of thioanisole see section on benzyl ether cleavage.)... 

Many carbamates have been used as protective groups. They are arranged in this chapter in order of increasing complexity of stmcture. The most useful compounds do not necessarily have the simplest stmctures, but are /-butyl (BOC), readily cleaved by acidic hydrolysis benzyl (Cbz or Z), cleaved by catalytic hy-drogenolysis 2,4-dichlorobenzyl, stable to the acid-catalyzed hydrolysis of benzyl and /-butyl carbamates 2-(biphenylyl)isopropyl, cleaved more easily than /-butyl carbamate by dilute acetic acid 9-fluorenylmethyl, cleaved by /3-elimination with base isonicotinyl, cleaved by reduction with zinc in acetic acid 1-adamantyl, readily cleaved by trifluoroacetic acid and ally], readily cleaved by Pd-catalyzed isomerisation. 

H2/Pd-C, 10 h, 87% yield. A nitrobenzyl carbamate is more readily cleaved by hydrogenolysis than a benzyl carbamate it is more stable to acid-catalyzed hydrolysis than is a benzyl carbamate, and therefore selective cleavage is possible. 

A -Dieiiol ethers are also formed by acid-catalyzed reaction of the steroid directly with benzyl alcohol with azeotropic removal of water/ Use of isooctane as azeotropic carrier may improve yields/ ... 

Acid-catalyzed dehydration of benzylic alcohols is a useful route to alkenylbenzenes, as is dehydrohalogenation under E2 conditions. 

Acid-catalyzed dehydration (Section 5.9) This is a frequently used procedure for the preparation of alkenes. The order of alcohol reactivity parallels the order of carbocation stability R3C" > R2CH " > RCH2 ". Benzylic alcohols react readily. Rearrangements are sometimes observed. 

BORIC ACID CATALYZED AMIDE FORMATION FROM CARBOXYLIC ACIDS AND AMINES N-BENZYL-4-PHENYLBUTYRAMIDE... 

The intermediates 74 and 76 can now lose OR to give the acid (not shown in the equations given), or they can lose OH to regenerate the carboxylic ester. If 74 goes back to ester, the ester will still be labeled, but if 76 reverts to ester, the 0 will be lost. A test of the two possible mechanisms is to stop the reaction before completion and to analyze the recovered ester for 0. This is just what was done by Bender, who found that in alkaline hydrolysis of methyl, ethyl, and isopropyl benzoates, the esters had lost 0. A similar experiment carried out for acid-Catalyzed hydrolysis of ethyl benzoate showed that here too the ester lost However, alkaline hydrolysis of substimted benzyl benzoates showed no loss. This result does not necessarily mean that no tetrahedral intermediate is involved in this case. If 74 and 76 do not revert to ester, but go entirely to acid, no loss will be found even with a tetrahedral intermediate. In the case of benzyl benzoates this may very well be happening, because formation of the acid relieves steric strain. Another possibility is that 74 loses OR before it can become protonated to 75. Even the experiments that do show loss do not prove the existence of the tetrahedral intermediate, since it is possible that is lost by some independent process not leading to ester hydrolysis. To deal with this possibility. Bender and Heck measured the rate of loss in the hydrolysis of ethyl trifluorothioloacetate- 0 ... 

Preparation of 2-fluorofuranoses is also important in relation to the synthesis of biologically active 2 -fluoro derivatives of nucleosides (see Section 111,4). Su and coworkers prepared the 2-triflates 236 and 239 through acid-catalyzed methanolysis of 3,5-di-O-benzyl-1,2-(9-isopropylidene-a-D-ribofuranose [to give 235 (major) and 238] and subsequent triflylation. On treatment with fluoride ion, the anomer 236 afforded exclusively the furan derivative 237, whereas the a anomer 239 gave the 2-fluoro compound 240... 

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