Acetaldehyde, the smallest enolizable aldehyde, has always proven a very challenging substrate and organocatalytic applications have not been the exception to this. In this context, the use of paraldehyde as an acetaldehyde precursor presents many advantages. For instance, the boiling point of the trimeric paraldehyde makes it much easier to handle, transport or store (123 ºC vs 21 ºC for acetaldehyde). Moreover, this species is cheaper than acetaldehyde itself. Thus, we hypothesized that the combination of the corresponding organocatalyst and an appropriated acid might enable the use of paraldehyde as an acetaldehyde precursor to be used in asymmetric catalysis. However, the required combination was not practical, as the strong acid was found to deactivate the aminocatalyst by salt formation. In other words, if we wanted to implement this strategy, we needed to find a way to provide shelter to a wolf and a lamb under the same roof.<br/><br/>Catalyst immobilization has been traditionally used to recover the catalytically active species with the aim of reusing it for as many cycles as possible. However, another added advantage is the fact that two functional groups that are incompatible in solution can easily co-exist in the same reaction media when they are independently supported onto a solid phase. In this work, site isolation has been applied to combine an organocatalyst (diphenylprolinol derivative) and a strong acid (polystyrene-bound sulfonic acid). Thus, while the latter carries out the deoligomerization of paraldehyde the former promotes the corresponding organocatalytic reaction.<br/><br/>Examples developed so far include the Michael addition of acetaldehyde to nitroalkenes and the cross-aldol reaction of aldehyde and electron-poor aromatic aldehydes. In the latter case, the catalytic pair has been reused ten times, good yields and excellent ee's being recorded in the last one. Finally, a strategy involving the use of the tricarbonylchromium complex of benzaldehyde has allowed the generation of its corresponding aldol products. These are interesting building blocks that can be easily derivatized to drugs such as Phenoperidine, Atomoxetine or Fluoxetine.

Paraldehyde as an acetaldehyde precursor: Site isolation of incompatible catalysts and use in asymmetric organocatalysis

250th National Meeting (2015)

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