P-Methoxybenzyl Acetate

For a series of methylbenzenes, the rates decreased in the order toluene > xylenes > mesitylene > durene > hexamethylbenzene. This order of reactivity is the reverse of that expected for a mechanism involving electrophilic substitution or electron transfer. However, Bushweller598 found that electron-releasing groups facilitate the benzylic oxidation of substituted toluenes by Pd(OAc)2 in acetic acid. p-Methoxy toluene gave a 96% yield of p-methoxybenzyl acetate, and p-nitrotoluene gave only 2% p-nitrobenzyl acetate, in agreement with either an electrophilic substitution or electron transfer mechanism. More mechanistic studies are necessary to clear up these anomalies. Steric effects may play an important role in these reactions. 

Heating toluene with lead tetraacetate at 80 °C for 54 h gives only 25% of benzyl acetate, but ethylbenzene and anisole give 63% of a-meth-ylbenzyl acetate after 16 h and 60% of p-methoxybenzyl acetate after 3 h at 80 °C, respectively [437]. Under similar conditions, acenaphthene yields... 

Benzylic oxidation of toluenes. Toluene is oxidized by palladium acetate (equimolar) in acetic acid at 90° (13 hrs.) to benzyl acetate (80% yield), benzaldehyde (4%) and benzylidene diacetate (6%) with formation of palladium (O).4 This oxidation is sensitive to electronic factors. Thus p-methoxytoluene is converted in 96% yield into p-methoxybenzyl acetate whereas p-nitrotoluene is essentially inactive. 

In a third variant on this theme, methyl 3,4,6-tri-O-benzyl-l-thio-a-D-mannopyranoside is converted into a p-methoxybenzyl acetal by first etherifying the 2-OH group with p-methoxyben/yl bromide and then treating the resulting p-methoxybenzyl ether with a hydroxyl compound in the presence of 2,3 -dichloro-5,6-dicyano-l,4-benzoquinone (DDQ). Activation of the methylthio anomeric center with methyl triflate then produces the (3-D-mannopyranoside as the only possible glycoside, again because of the acceptor being tethered to the (3 side of the mannopyranoside.56... 

Synonyms Acetic acid 4-methoxybenzyl ester 4-Methoxybenzyl acetate p-Methoxybenzyl acetate... 

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). 

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. 

The p-methoxybenzylidene ketal can be prepared by DDQ oxidation of a p-methoxybenzyl group that has a neighboring hydroxyl. This methodology has been used to advantage in a number of syntheses. " In one case, to prevent an unwanted acid-catalyzed acetal isomerization, it was necessary to recrystallize the DDQ and use molecular sieves. The following examples serve to illustrate the reaction " ... 

The free base 13 is obtained by stirring with sodium acetate in MTBE. Benzylation by treatment with a mild acid and p-methoxybenzyl alcohol provides 14 (Emert et al., 1977 Henneus et al., 1996). The initial conditions for the asymmetric addition of the lithium acetylide to the trifluoroketone appear in an earlier Merck paper (Thompson et al., 1993, 1996). Optimization of these conditions, which include some elaborate NMR studies (Thompson et al., 1998) and key scale-up experiments, provides a reliable and scaleable procedure to install the stereocenter in high yield, purity, and enantioselectivity (Scheme 6.3). n-Butyllithium (or w-hexyllithium, minimum four equivalents) is added to a solution of (lR,25)-A-pyrrolidinylnorephedrine (Corey and Cimrich, 1994) (two equivalents) and cyclopropylacetylene (two equivalents) at — 10°C and the reaction is allowed to warm to 0°C. These conditions are critical to establish the chiral complex that is responsible for the high enantioselectivity. This solution is cooled below — 50°C, and trifluoroketone 14 in THE is added and stirred for about 1 h at this temperature before... 

Removal of the p-methoxybenzyl group is accomplished by treatment with dichloro-dicyanoquinone (DDQ), which forms quantitatively aminal 17 in an 11.5 1 diastereomeric ratio (Yu and Levy, 1984). The solution is treated with sodium methoxide in methanol, which decomposes the aminal into the desired amine 18 and p-methoxybenzaldehyde. Due to the difficulties in separating the p-methoxybenzaldehyde from amino alcohol 18, the aldehyde is reduced in situ with sodium borohydride. The amino alcohol 18 is crystallized from the reaction mixture after neutralization with acetic acid. Additional recrystallization provides the desired amino alcohol 18 in 94% yield. 

C s -lodomethylcephalosporins. C3-Acetoxymethyl- or C3-carbamoylmethylce-phalosporins (1) are converted to C3-iodomethylcephalosporins (2) on reaction with lSi(CH3)3 in CH2C12 at 20°. The ester group in 1 is not cleaved if it is benzyl or t-butyl, but p-methoxybenzyl or benzhydryl esters are cleaved faster than the allylic acetate group. This reaction is observed with both A2- and A3-cephems.5... 

An attractive alternative strategy Scheme 3.20) for the synthesis of (88b) focused on the conversion of a 3-formylthietane acetal (99) to an unsymmetri-cally substituted isobutyraldehyde acetal (100) via alkylative ring opening with p-methoxybenzyl bromide. Several subsequent steps produced a mixture of (101) and (102) which could not be fully aromatized to (102) owing to extraordinary insolubility, which, unfortunately, ultimately precluded synthesis of (88b) by this route. 

In another study by Dondoni et al. [17] the synthesis of C-glycosyl-/ -aminoesters as single diastereomers is achieved via a Mannich-type three-component reaction of /Minked C-galactosyl or C-ribosyl formaldehyde, p-methoxybenzyl amine and ketene silyl acetals using catalytic amounts of InCfi (Scheme 9.8). 

An intermediate in the synthesis of laulimalide by Davidson8 illustrates the differential protection of alcohols. The starting materials 56 and 57 already have an alcohol protected as a TBDMS silyl ether and a diol protected as an acetal. The alcohol in 58 is protected as a p-methoxybenzyl ether and the acetal hydrolysed by acetal exchange to give the free diol 60. Selective protection of the primary alcohol by a bulky acyl group (pivaloyl, i-BuCO ) 61 allows silylation of the secondary alcohol with a TIPS group 62. Finally the pivaloyl group is selectively removed by DIBAL reduction to release just one free alcohol 63. 

Later on, all the protecting groups will be removed the silyl groups with fluoride and the p-methoxybenzyl ether by oxidation with Ce(IV). In Ley s recently completed synthesis9 of azadirachtin 64 after 22 years of hard labour the key intermediate was 65. You will notice benzyl ethers, acetals and a silyl ether. This is a more modem, one might almost say minimalist, use of protection. In an ideal world no protecting groups would be necessary but in a real synthesis they will almost certainly be required as we shall see in the rest of the book. But our aim should be to keep them to a minimum. 

The same electron transfer mechanism was proposed by Heiba et a/.242 247 and was supported by the observation by ESR of the radical cations of several arenes when they were treated with Co(III) acetate in trifluoracetic acid.248 Cobalt(III) is a stronger oxidant in trifluoracetic acid than in acetic acid217,249 (see later). In some cases (with electron-rich aromatics), radical cations were observed in acetic acid.242 Further evidence for the radical cation mechanism was obtained in the oxidation of p-methoxybenzyl phenyl sulfide.242 The pro-... 

D-Galactal Acetal Benzene TBAB 80 p-Methoxybenzyl chloride — 70 0 182... 

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