Hydroformylation-aldol reaction

The aldol reaction is probably one of the most important reactions in organic synthesis. In many industrially important hydroformylation processes selfcondensation of aldehydes is observed. Sometimes this consecutive reaction is favored as in the production of 2-ethyl hexanol. But synthetic applications of tandem hydroformylation/aldol reactions seem to be limited due regiose-lectivity problems of a mixed aldol reaction (Scheme 28). However, various tandem hydroformylation/intramolecular mixed aldol reactions have been described. 

Scheme 28 Basic principle of the hydroformylation/aldol reaction...

This method can also be applied to silyl enol ethers of homologous unsaturated ketones as well as of unsaturated aldehydes or esters [85-87]. While unmodified unsaturated esters give only the corresponding aldehydes without cyclization under tandem hydroformylation/aldol reaction conditions, the corresponding silylated ester enolates smoothly cyclize in a tandem hy-droformylation/ Mukaiyama aldol reaction (Scheme 32) [85-87]. 

Very recently, a tandem sequence consisting of enolboration/hydroform-ylation/aldol reaction has been described [88]. Here configuration of the enol boronate is transferred to the aldol product, allowing good to excellent di-astereoselectivities in the hydroformylation/aldol reaction. With this method, 5-7-membered rings are obtained in excellent yields (Scheme 35). 

SUylenol ethers such as 184 also undergo the hydroformylation-aldol reaction to give the sUylated aldol adducts 185 in good yields through a sequence of reactions involving the hydroformylation of the alkene and the intramolecular Mukaiyama type aldol reaction. [108]. Best results were achieved using the trimethylsilyl group. 

Figure 46. Consecutive hydroformylation-aldol reactions in the presence of amines...

Hydroformylation of olefins has been established as an important industrial tool for the production of aldehydes. In recent years, novel asymmetric tandem reactions have included a rhodium-catalysed enantioselective hydroformylation. In this context, in 2007 Abillard and Breit ° and Chercheja and Eilbracht independently reported a novel domino hydroformylation-aldol reaction catalysed by an achiral rhodium catalyst and L-proline catalyst (Scheme 7.49). Possibly owing to the fact that proline is hard but the rhodium catalyst is soft, the proline can be compatible with the rhodium catalyst to allow this domino reaction to be achieved. By fine adjustment of the hydroformylation rate to that of the L-proline-catalysed aldol addition, the undesired homodimerisation of the aldehyde could be avoided. As a result, by in situ hydroformylation reaction, the donor aldehyde of a... 

Later, Eilbracht et al. developed a related enantioselective domino hydroformylation-aldol reaction catalysed by a rhodium complex in combination with a chiral amine derived from L-proline. In this process, the reaction of acetone with vinylbenzene afforded the corresponding chiral p-hydrojgr ketone in 69% yield, a moderate diastereoselectivity of 74% de, and a high enantioselectivity of 93% ee, as shown in Scheme 7.50. ... 

Scheme 7.49 Domino hydroformylation-aldol reaction catalysed chiral amine catatysis and rhodium catalysis.

The one-pot hydroformylation/aldol reaction sequence was applied to unsaturated ketones and ketoesters in the presence of a rhodium catalyst to afford the corresponding carbocydic aldol adducts in good yields (Equation 7.12) [134]. 

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