Base-promoted acetal formation employing aryl salicylates

New examples of base-promoted acetal formation in the reactions of aryl salicylate and salicylate-type esters 1 to 3 with aldehydes are reported.


Introduction
Recently we reported that aryl esters of 2-hydroxybenzoic acids (i.e.salicylates) form cyclic acetals with a variety of aldehydes (scheme 1) under base-catalyzed conditions. 1 Key aspects of the process were that the reactions worked best under neat conditions or, where necessary, with minimal solvent to effect dissolution.This is in contrast to most methods for acetal formation which usually employ acid-catalyzed conditions.

Scheme 1
Herein we provide further examples of this process as well full experimental details for these new cases as well as the first successful reaction with an aromatic aldehyde.

Results and Discussion
Oxo-acetal formations of esters 1 to 3 were investigated.The structures of the starting materials and products are shown in Figure 1.Most reactions were carried out neat except where either, or both, the aldehyde and salicylate were solids.In those cases a very small volume of chloroform was added to effect solution.The ratio of reactants was salicylate: aldehyde: base = 1 : 5 : 1.

Figure 1
As before aliphatic aldehydes, solid paraformaldehyde and chloral all reacted well with esters 1 to 3. In our previous report we noted that the use of aromatic aldehydes did not lead to successful reaction.Interestingly we have now discovered one exception to this, namely reaction of phenyl 4-methoxysalicylate (1).Reaction with benzaldehyde under standard conditions gave oxo-acetal 4e in 49% yield.Only in one case, that of salicylate 5 was any product formed in a reaction with an unsaturated aldehyde (cinnamaldehyde).The yield was very low (8%).Hence it can be concluded that, in general, unsaturated aldehydes (including aromatic aldehydes) are not usually good substrates for this process.
A brief investigation was carried out to examine whether any diastereoselectivity would occur in reactions with the chiral, non-racemic aldehyde, D-glyceraldehyde acetonide 2 .Hence 2 was reacted with D-glyceraldehyde acetonide.This provided an essentially 1:1 diastereomeric mixture of acetals 7. Unfortunately this mixture proved to be inseparable.