Benzylic oxygenated substituents

Compounds containing both benzylic and homobenzylic oxygenated substituents may lose either or both functions on hydrogenolysis, in proportions that depend on the catalyst, stereochemistry of the starting material, and substituents (38,54,64,119,183). 

The two free hydroxy groups are First protected with acetic anhydride. In a second step the acetyl group is reductively cleaved by a Birch reduction with lithium in liquid ammonia.19 Lithium dissolves in the ammonia with the formation of solvated electrons. Stepwise electron transfer to the aromatic species (a SET process) leads first to a radical anion, which stabilizes itself as benzylic radical 38 with loss of the oxygen substituent. A second SET process generates a benzylic anion, which is neutralized with ammonium chloride acting as a proton source (see Chapter 12). 

Occasionally there is a carbon or an oxygen substituent found on the alpha-carbon atom of the benzyl group. This is taken into account in the alphabetization. These substituents have the following priority ... 

Combining the above values of pAR with the value for the p-methoxybenzyl cation measured by Toteva and Richard158 allows the effect of the three oxygen substituents on the stability of the benzyl cation to be compared in Scheme 22. The values of pAR may also be compared with effects of similar oxygen substitutions at the a-position of the benzyl cation from Table 3, which are also shown in Scheme 22. As expected, the relative magnitudes of the O-, HO, and MeO substituent effects exhibit similar patterns in the a- and... 

Table 4 Effects of oxygen substituents on stabilities of cyclic benzylic carbocations...

In related investigations Valderrama et al. [47] studied the reaction of naphthoquinone (40) and juglone (47) with the ketene acetal 51. Using this oxidation state, the oxygen substituent in the product is always preserved at the terminal position of dienes (compare anthracycline chemistry [55]). Thus, the phenol ether 52 a (61 %) and smaller amounts of the phenol 52b were smoothly formed after silica gel-promoted elimination and air oxidation of the primary Diels-Alder adducts. The authors also observed base-catalyzed air oxidation to the ketone 53, analogous to similar oxidations of benzylic carbanions (compare with [56]). 

As a general rule, oxygen substituents are lost from benzylic positions during metal-ammonia reductions. An important set of exceptions are those compounds which possess a methoxy group in a para relationship to the benzylic substituent. Thus, 4-methoxybenzyl alcohol (208) may be reduced in high yield... 

Both tetrahydroisoquinoline amides and formamidines may be successively alkylated at the l-posi-tion. The second deprotonation is somewhat less facile, however, since it entails removal of a methine proton. In applying this methodology to the synthesis of naturally occurring tetrahydroisoquinoline alkaloids, a problem is encountered. The presence of oxygen substituents on the aromatic ring destabilizes the benzylic carbanion, and since this effect is felt in the transition state, the acidity of the benzylic protons is lowered. Thus, successive alkylation of t-butylformamidines of oxygenated tetrahydroisoquinolines is not possible. To circumvent the decreased acidity, a study of the relative acidity of various N-substituted formamidines was done- that resulted in a solution to the problem. As shown in Scheme 15, successive alkylation of the methoxymethylphenylformamidine (9) is readily achieved. 

A novel approach to stereocontrol in 2,3-Wittig rearrangements involves the use of chiral chromium tricarbonyl complexes (Table 8a). The reactions, which were carried out with racemic ethers, show excellent diastereoselectivity as a consequence of a preferred transition state in which the benzylic oxygen and the R -substituent and the vinylic grouping and Cr(CO)3 grouping adopt anti orientations (Lc). 

A mechanism of this type permits substitution of certain aromatic and ahphatic nitro compounds by a variety of nucleophiles. These reactions were discovered as the result of efforts to explain the mechanistic basis for high-yield carbon alkylation of the 2-nitropropane anion by p-nitrobenzyl chloride. p-Nitrobenzyl bromide and iodide and benzyl halides that do not contain a nitro substituent give mainly the unstable oxygen alkylation product with this ambident anion ... 

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