Methoxymethyl acetal

The lithiation of phenols protected as acetals—methoxymethyl acetals like 140 in particular—is especially valuable the second oxygen supplies a powerful coordination component to their directing effect (Scheme 69) The regioselective lithiation of 141 was used in the synthesis of the pterocarpans 4 -deoxycabenegrins A-I. 

Methoxyacetonitrile showed exclusive coordination at the methoxy oxygen while methoxymethyl acetate indicated interactions with BF3 at both the ether and the carbonyl oxygens. Interestingly, a large difference was observed in the preferred site of coordination between methyl methoxyacetate and methoxymethyl acetate (equations 1 and 2). The apparent lower basicity of the ether oxygen in the latter was attributed to the electron-withdrawing effects of the proximal acetate group. 

The acetal cleavage mechanisms sketched out in Schemes 2.15-2.19 have been written - for simplicity - as leading to oxocarbocations. This is likely to be the case for acetals derived from benzaldehyde or tetrahydropyran, but nucleophilic participation by the solvent is undoubtedly involved in the reactions of methoxymethyl acetals, and most likely in those of most glycosides. This aspect is discussed in more detail in Section 2.3.3 below. 

The most efficient system of this sort - and the only one to show intramolecular general acid catalysis of the hydrolysis of a methoxymethyl acetal derived from an aliphatic alcohol - is compound 3.13, based on the most reactive aromatic system... 

Compound 3.13 (Scheme 2.22) is hydrolyzed with a half-life of 3.5 h in water at 39 °C, some 10 times faster than expected for the spontaneous hydrolysis of a methoxymethyl acetal of a tertiary alcohol, corresponding to a transition state stabilization of 14 kcal (58 kj) mol [47], and at the rate expected for the methoxymethyl derivative of an alcohol of pKa about 4. Perhaps significantly, this is almost equal to the pKa (4-18) of the catalytic COOH group of 3.13. (Which also confirms that there is no significant intramolecular hydrogen bonding in the reactant.)... 

As discussed above (Section 2.2.2) the hydrolysis reactions of glycosides and methoxymethyl acetals involve nucleophilic participation by water. If water can act as a nucleophile in these systems then reactions with other, better nucleophiles are to be expected. (The model, and the inspiration for most work in this area is the enzyme lysozyme which - like retaining glycosidases in general - uses two carboxyl groups, one acting as a nucleophile, the other as a general acid, to accomplish (exo-... 

This picture is general for reactions of methoxymethyl acetals and glycosides with any nucleophile, including solvent water. Estimates of the lifetimes of the free oxocarbocations that would be involved in unimolecular processes suggest that they would be too short, or at best borderline, for them to exist in water and definitely too short in the presence of a better nucleophile than water. (For a succinct review of this topic see Davies et al. [48].)... 

F.18) Methanol, methoxy-, acetate, methoxymethyl acetate, acetate de methylmethoxy 4382-76-7]... 

In view of the described effects of substitution on heterolytic bond cleavage rate and on the scissile bond length, it is not surprising that this bond distance is correlated with reactivity and that the correlation holds for variation at both ends of the bond. Indeed, Jones and Kirby point out that there are excellent linear correlations of log with intercepts and slopes of the corresponding bond length-pAfa plots for the series a-glucosides, methoxymethyl acetals, and axial tetrahydropyranyl... 

Secondary fragments are formed from the primary ones by single or consecutive eliminations of formaldehyde (30), methanol (32), ketene (42), acetic acid (60), methyl acetate (74), methoxymethyl acetate (104), or acetoxymethyl acetate (132). Mechanisms for elimination of formaldehyde from the primary fragment m/e 89 have already been described (see Section IV,3 p. 57), as well as those for the elimination of acetic acid (60) and the subsequent elimination of ketene (42) (see Section IV,1 p. 53). 

Some secondary fragments are best explained by elimination of methoxymethyl acetate (see Scheme 16) and acetoxymethyl acetate (see Scheme 17), respectively. 

The argument is based on the explicit assumption that for each mechanism, the activation parameters are uninfluenced by temperature. The authors feel this assumption to be permissible in view of the constancy of these parameters in the case of the acid hydrolysis of methoxymethyl acetate and ethoxymethyl acetate. The plausibility of this assumption will be discussed in the next section. 

The acid-catalyzed hydrolysis of simple partial acylals has been studied in condensed phase, " " and a study of the behavior of methoxymethyl formate and methoxymethyl acetate in chemical ionization mass spectrometry was undertaken " to provide a comparison of the gaseous and solution phase chemistry of these simple partial acylals. Methoxymethyl formate and methoxymethyl acetate undergo hydrolysis in aqueous acid by an A lI mechanism,... 

The spectra of methoxymethyl formate are very similar to those of methoxymethyl acetate, but again with one significant difference. A fairly intense (M — 3) ion is observed in the acetate ester at mje = 101, but in the formate ester none of this ion is observed. However, the most intense ion in the spectrum (relative intensity = 51%) is mje = 101, which is the same mje value as is found for the (M — 3) ion in the acetate ester. From a study... 

TABLE XVI. Chemical Ionization Mass Spectra of Methoxymethyl Acetate and Isobutane Reactant ... 

Obtained by condensation of 2,4-di-propionylphlorogluci-nol with 40% formaldehyde [8404], (58-65%) [6879] or with methoxymethyl acetate in acetic acid in the presence of few drops of concentrated sulfuric add [8405]. 

---