P-Methoxy-benzyl alcohol

During the reaction of p-methoxy benzyl alcohol with silyl enol ether 31b, dibenzyl ether 33 was observed as a by-product, which disappeared after prolonged reaction time. In fact, if 33 was used as alkylating reagent, the silyl enol ether 31b was benzylated and the desired cyclopentanone 32e was obtained in a similar yield (Scheme 25). 

Esterification with the dineopentyl acetal is very slow (benzoic acid, 80° in benzene, 1 hr —7% yield of ester) and this reagent is used conveniently as a catalyst in the direct esterification of acids and alcohols (benzyl and p-methoxy-benzyl alcohol) where for the alcohol k kneope tyi. Trans-acetalization occurs initially via the reaction (a). 

The sodium alkoxides prepared from primary and secondary alcohols and sodium hydride in a mixture of THF and DMF or DMSO react with p-methoxy-benzyl chloride at room temperature to give the p-methoxybenzyl ethers in good yield. Use of THF alone is not so satisfactory. p-Methoxybenzyl chloride (nip -1 °C bp 117 C/L9 kPa) is moisture sensitive and deteriorates on standing so it should be freshly distilled in vacuo before use. In sluggish reactions, the rate can be increased by the addition of a catalytic amount of tetrabutylam-... 

Methyl, ethyl, benzyl, benzhydryl, p-nitrobenzyl, p-methoxy-benzyl, 4-picolyl, j3j -trichloroethyl, j3-methylthioethyl, /J-p-toluenesulphonylethyl, and -p-nitrophenylthioethyl esters may be prepared directly from the acid and alcohol. TTie most usual method [4, 5] consists of heating the acid and an excess of the alcohol with an acid catalyst (e.g., Fischer-Speier, hydrochloric or sulphuric acid). The extent of reaction is improved if the water formed is removed by azeotropic distillation with an inert solvent (benzene, carbon tetrachloride, or chloroform). Considerable variation is possible in the natvire of the acid catalyst thus phosphoric acid [6], aryl sulphonic acids [7, 8, 9], alkyl sulphates [10], and acidic ion-exchange resins [11] may be employed. Removal of the water by azeotropic distillation during the formation of methyl esters is difficult and Brown and Lovette [12] introduced the novel reagent acetone dimethyl acetal (7) for the direct formation of methyl esters. In the presence of a trace of methanol and an acid catalyst the reagent acts as a scavenger of water formed by esterification and liberates further methanol for reaction. 

The addition of anilines to styrene oxide was reported to also proceed in the presence of 10mol% 37 affording the corresponding P-amino alcohols 1-5 in yields ranging from 75% to 92% (Scheme 6.37). Additionally, urea derivative 37 (20mol% loading) was found to catalyze the addition of aniline (2.0 equiv.) to ( )-stilbene oxide (92% yield 5.9 d 30°C), the addition of thiophenol (2.0 equiv.) to 2-methoxy styrene oxide (85% 20h rt), and the alcoholysis of 4-methoxy styrene oxide with benzyl alcohol (2.0 equiv.) affording the respective P-alkoxy alcohol (82% 20h rt). 

A 1,2-hydride shift has been invoked399 to account for the formation of p-methoxyphenylbutyraldehyde derivatives (337) during the treatment of />methoxy-benzyl-protected allylic alcohols (336) with zeolites. A similar C-glycosidation procedure involving Lewis acid-catalysed anomeric oxygen to carbon rearrangement of tetrahydropyranyl ether derivatives has been reported400 (see Scheme 82). It has been... 

The parallelism in reactions with HMPT and mixtures of phosphorus pentoxide and amines can best be realized by looking at the mechanism of HMPT reactions [1 5 ]. In the reaction of p-methoxy-benzylalcohol with HMPT which produce the corresponding N,N-dimethylbenzyl amine--p-methoxybenzyl phosphate was identified in the XP NMR spectrum of the reaction mixture. Since pyrophosphate was also observed during the reaction of the benzyl alcohol with HMPT, the intermediate formation of the metaphosphate anion can be assumed. Addition of the benzyl alcohol to that anion then produce the benzyl phosphate. Phosphate ions are known to be good leaving groups so that a benzylamine can easily be produced from the phosphate by reaction with di-methylamine released from the dimethylammonium ion. The phosphoric acid produced during the reaction is believed to react with HMPT, so that more dihydro-gen-bis(dimethylammonium) pyrophosphate is formed. 

This effect of the p-methoxy group in promoting the homologation reaction is consistent with its similar effect in the benzyl alcohol series. The isolation of the alcohol is also additional evidence for the intermediate formation of a carbinol in the reduction of an aromatic ketone to the hydrocarbon. 

Another hybrid protecting group is the p-[(trimethylsilyl)ethoxy]methoxy benzyl (p-SEM-benzyl) ether354 Phenolate anions generated by treatment of p-SEM-benzyl ethers with TBAF in DMF at 80 °C eliminate to give the deprotected alcohol as illustrated in Scheme 4.303 p-SEM-benzyl ethers are compatible with many of the standard manipulations in oligosaccharide synthesis and they arc orthogonal to benzyl and p-methoxybenzyl ethers. 

Mergler, M., Nyfeler, R., Tanner, R., Gosteli, J., and Grogg, P. (1988) Peptide synthesis by a combination of solid-phase and solution methods II synthesis of fully protected peptide fragments on 2-methoxy-4-aIkoxy-benzyl alcohol resin, Tetrahedron Lett. 29, 4009—4012. 

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