Benzyl alcohol solvolysis

It is important to note that the one-step conversion of 27 to 28 (Scheme 4) not only facilitates purification, but also allows differentiation of the two carbonyl groups. After hydrogenolysis of the iV-benzyl group (see 28—>29), solvolysis of the -lactone-ring in 29 with benzyl alcohol and a catalytic amount of acetic acid at 70 °C provides a 3 1 equilibrium mixture of acyclic ester 30 and starting lactone 29. Compound 30 can be obtained in pure form simply by washing the solid mixture with isopropanol the material in the filtrate can be resubjected to the solvolysis reaction. 

With the methylated PAHs, another bioactivation pathway leading to benzylic carbocations becomes available through side chain oxidation to form a benzylic alcohol, followed by esterification and solvolysis. Thus, benzylic sulfate ester formation (via initial formation of benzyl alcohol) constitutes an additional route that could contribute to metabolic activation (Fig. 2). ... 

Although an appreciable amount of p-tolualdehyde was formed in oxidations with and without bromide, relatively little p-methylbenzyl alcohol and acetate resulted in the absence of bromide (1/10 to 1/25 as much as with bromide ion). The contrasting results suggest that the benzyl alcohol is a minor product in the autoxidation chain, as previously postulated by Boland, Bateman, and others (4, 7, 8, 15, 27), and is formed in the presence of bromide by solvolysis ... 

Polystyrene-bound allylic or benzylic alcohols react smoothly with hydrogen chloride or hydrogen bromide to yield the corresponding halides. The more stable the intermediate carbocation, the more easily the solvolysis will proceed. Alternatively, thionyl chloride can be used to convert benzyl alcohols into chlorides [7,25,26]. A milder alternative for preparing bromides or iodides, which is also suitable for non-benzylic alcohols, is the treatment of alcohols with phosphines and halogens or the preformed adducts thereof (Table 6.2, Experimental Procedure 6.1 [27-31]). Benzhy-dryl and trityl alcohols bound to cross-linked or non-cross-linked polystyrene are particularly prone to solvolysis, and can be converted into the corresponding chlorides by treatment with acetyl chloride in toluene or similar solvents (Table 6.2 [32-35]). 

Aliphatic alcohols do not undergo solvolysis as readily as benzylic alcohols, and are generally converted into halides under basic reaction conditions via an intermediate sulfonate. Because of the hydrophobicity of polystyrene, however, nucleophilic substitutions with halides on this support do not always proceed as readily as in solution (Table 6.3). Alternatively, phosphorus-based reagents can also be used to convert aliphatic alcohols into halides. 

A situation of this type was encountered in the investigation of the solvolysis of benzyl azoxytosylate, 14 in Fig. 9.6, in aqueous trifluoroethanol [23]. In the absence of added nucleophilic reagents the products were benzyl alcohol and benzyl trifluoroethyl ether. Added excess sodium thiocyanate had minimal effect upon the rates, but the reaction then yielded substantial amounts of benzyl thiocyanate. The plot of the inverse mole fraction of benzyl thiocyanate against 1/ [NaSCN], shown in Fig. 9.6, is linear with a non-zero intercept, consistent with the intermediacy of a species trappable by thiocyanate, and a competing pathway for the formation of ethereal and alcoholic products other than via this species. 

Gurtius and co-workers studied the acid-catalysed decomposition of alkyl azides such as benzyl azide. This was decomposed in either warm 1 1 (v/v) sulphuric acid-water or with concentrated hydrochloric acid to give a mixture of products corresponding to hydrogen migration [benzaldiinine (1)], phenyl migration [formaldehyde anil (2)], the azide reduction product [benzylamine (3)], and the solvolysis product [benzyl alcohol (4)]. The first two were obtained as the... 

The reason for the low reactivity of dibenzyl phosphate is that it cannot expel benzyl alcohol to form metaphosphate. Therefore, the solvolysis must proceed by nucleophilic attack of hydroxide on the dibenzyl phosphate monoanion or attack of water on the neutral, acidic dibenzylphosphoric acid. 

Several syntheses are available to the 13,14-dihydroprostaglandins, some of which are metabolites of the E and F series. The first of these routes [143, 144] started from the formyl derivative (LVII) of the enol ether of cyclo-pentan-l,3-dione which on reaction with ethyl 6-bromosorbate and tri-phenylphosphine followed by selective catalytic reduction afforded the ester (LVIII). A second formylation followed by elaboration with n-hexanoyl-methylenetriphenylphosphonium chloride 1 to the ketone (LIX) which on reduction of the exocyclic double bond and acid-catalysed solvolysis in benzyl alcohol afforded the benzyl ether (LX) and its isomeric enol ether. Reduction with lithium tri-t-butoxyaluminium hydride to the corresponding 15-hydroxy-compound and palladium-charcoal catalysed hydrogenolysis followed by prolonged catalytic hydrogenation with rhodium-charcoal led to ( )-dihydro-PGEi ethyl ester. 

The oxirane ring in 175 is a valuable function because it provides a means for the introduction of the -disposed C-39 methoxy group of rapamycin. Indeed, addition of CSA (0.2 equivalents) to a solution of epoxy benzyl ether 175 in methanol brings about a completely regioselective and stereospecific solvolysis of the oxirane ring, furnishing the desired hydroxy methyl ether 200 in 90 % yield. After protection of the newly formed C-40 hydroxyl in the form of a tert-butyldimethylsilyl (TBS) ether, hydrogenolysis of the benzyl ether provides alcohol 201 in 89 % overall yield. 

With ring G in place, the construction of key intermediate 105 requires only a few functional group manipulations. To this end, benzylation of the free secondary hydroxyl group in 136, followed sequentially by hydroboration/oxidation and benzylation reactions, affords compound 137 in 75% overall yield. Acid-induced solvolysis of the benzylidene acetal in 137 in methanol furnishes a diol (138) the hydroxy groups of which can be easily differentiated. Although the action of 2.5 equivalents of tert-butyldimethylsilyl chloride on compound 138 produces a bis(silyl ether), it was found that the primary TBS ether can be cleaved selectively on treatment with a catalytic amount of CSA in MeOH at 0 °C. Finally, oxidation of the resulting primary alcohol using the Swem procedure furnishes key intermediate 105 (81 % yield from 138). 

Benzyl carbamate protection (Cbz or Z group see Table 10.15) was initially chosen by Merrifield for solid-phase peptide synthesis [255], The strongly acidic conditions required for its solvolysis (30% HBr in AcOH, 25 °C, 5 h) demanded the use of an acid-resistant nitrobenzyl alcohol linker. Z-protection of the a-amino group in solid-phase peptide synthesis was, however, quickly abandoned and replaced by the more acid-labile Boc protection. Benzyl carbamates can be cleaved by strongly ionizing... 

These predictions were found to be correct for benzyl and o- and p-methylbenzyl cations, generated by solvolysis of the corresponding tosylates in bicarbonate buffered acetonitrile/water mixtures (Cedheim and Eberson, 1969). With 3% (w/w) water present, essentially all of the product was the alcohol (Fig. 5) from these data it can be estimated that water is 40-50 times more reactive as a nucleophile than acetonitrile towards cations. 

In particular, minima in plots of AV against x2 are not necessarily due to the trend in the initial state quantity, and volumetric data can provide some indication of the details of reaction mechanism. Thus for the hydrolysis of p-chlorobenzyl chloride (Sn2), a shallow minimum in 5mAF for reaction in aqueous ethyl alcohol stems from a more intense maximum in 8m than for 5mF. At the other end of the scale, a sharp minimum in 8mAF for t-butyl chloride solvolysis (SnI) results from a sharp minimum in SmF, 5m V3 changing only gradually as x2 is increased. The behaviour of the volumetric properties for the benzyl... 

Figure 51. Dependence of volume parameters for the solvolysis of benzyl chloride on mole fraction of alcohol in ethyl alcohol + water mixtures at 323 K (Mackinnon et al., 1970).

Solvolysis of electrophilic cyclopropanes with alcohols and phenols readily occurs as illustrated by the following examples of equations 166-168. It is worthwhile to note that methanolysis at 126 °C of ( + )-( ) methyl l-cyano-2-phenylcyclopropanecarboxylate (495) gives rise to (— )-(S)-methyl 2-cyano-4-methoxy-4-phenylbutanoate (496), indicating that the nucleophilic substitution reaction at the benzylic carbon of the cyclopropane proceeds with essentially complete inversion of configuration (equation 169). ... 

The synthesis of prodrug 13 first involved condensation of penta-0-acetyl-D-galactose (15) with para-cresol (16), in the presence of ZnCl2 [56, 57], to afford stereospecifically the a-glycoside 17 [58]. Benzylic bromination of 17 was achieved by treatment with iV-bromosuccinimide in carbon tetrachloride under photolysis conditions. Solvolysis of the bromobenzyl derivative 18 by treatment with silver nitrate in a mixture of acetone and water afforded alcohol 19 [59], which was subsequently activated through reaction with A -hydroxysuccinimidocarbonate to 20. 

Hydrolysis of the galactosyl unit of 52 would produce a bis-carbamate intermediate. After release of C02, the resulting para-aminobenzylcarbamate, known to undergo spontaneous 1,6-elimination (52) under mild conditions, should lead to free doxorubicin (2) and another molecule of C02. Synthesis of prodrug 52 involved initial condensation of 2,3,4,6-tetra-O-acetyl-a-D-galactopyranose (49) with para-tolyl isocyanate in DMF to afford carbamate 53. Benzylic bromination of 53 to 54 was followed by solvolysis into primary alcohol 55. Activation of 55 to 56 was achieved by use of 4-nitrophenyl chloroformate. Further condensation of 56 with doxorubicin (2) in DMF gave 57 which was finally deprotected by transesterification to yield prodrug 52 [63]. 

Solvation-based discrepancies in reactivity are not limited to gas phase-solution comparisons. In alcohol solutions, a cyclopropyl group will generally increase the rate of an Sjyl solvolysis more than a phenyl. By use of NMR, Olah and co-workers have clearly shown that in superacid solutions, benzyl cations have higher electron densities on the a carbon than their cyclopropyl carbinyl analogs. ... 

Reminiscent of the effects encountered in the corresponding allylic systems (Section 14-3), benzylic resonance can affect strongly the reactivity of benzylic halides and sulfonates in nucleophilic displacements. For example, the 4-methylbenzenesulfonate (tosylate) of 4-methoxyphenylmethanol (4-methoxybenzyl alcohol) reacts with solvent ethanol rapidly via an SnI mechanism. This reaction is an example of solvolysis, specifically ethanolysis, which we described in Chapter 7. 

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