Synthesis of para-substituted cinnamaldehydes as substrates in aminocatalyzed aldol reactions with ketones

Abstract

One of the most important challenges in organic chemistry is the stereoselective formation of C–C bonds using sustainable methods that follow the principles of Green Chemistry. Organocatalytic aldol reactions are especially useful in this regard since a new C–C bond is formed and up to two new stereocenters can be created using nontoxic small organic molecules as catalysts under mild reaction conditions. The main aim of the project of our research group is to develop aminocatalytic aldol reactions of ketones to α,β-unsaturated aldehydes. In this work, p-nitrocinnamaldehyde and p-trifluoromethylcinnamaldehyde have been prepared via the Julia–Kocienski and Wittig reactions, to determine which is the best method to prepare them. Although the Julia–Kocienski method led to the desired aldehyde as a single E-diastereomer with good yields, it needs harsh conditions and prior preparation of the sulfone. In contrast, the Wittig reaction is more straightforward and needs milder conditions, but it produces mixtures of E and Z isomers. To overcome this limitation, isomerization methods were explored. The use of iodine at rt with sunlight proved effective, enriching the E isomer in a practical and scalable way. We have also studied the reactivity of the synthesized aldehydes in organocatalytic aldol reactions using L-proline tetrazole as catalyst. Acetone and cyclohexanone were tested as nucleophilic donors. In the acetone case, the desired aldol product was obtained with a 24% yield. Since the yield was relatively low, different hydrogen bond donors were tested as additives to improve the outcome of the reaction, but none of them led to product formation under the conditions tested