Hydroformylation-aldol

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...

In almost the same manner, tandem hydroformylation/aldol condensation aldol condensation of ketoolefins, such as p,y-unsaturated ketones, gives a single cyclization product under acid catalysis. Similar to the stepwise reaction, the in situ generated aldehyde preferentially acts as the electrophilic carbonyl component, while the ketone acts as the nucleophilic enol to form the five-membered ring product. Subsequent dehydration and hydrogenation of the resulting enone readily occurs under the reductive reaction conditions used (Scheme 30) [84],... 

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]. 

Similarly, tandem hydroformylation/aldol sequences can be applied to the formation of bicyclic and spirocyclic compounds. Thus silyl enol ethers of 3-vinyl and 3-allyl cycloalkanones give ring anellated products (Scheme 33) [86,87]. 

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). 

In a similar manner, the cyclohydrocarbonylation of A -l-allyl-2-formylpyrrole 80a-c afforded 7-formyl-5,6-dihydroin-dolizine 84a-c in good yield through one-pot cascade hydroformylation-aldol condensation process (Scheme 13)." ... 

Raffinate-2 as a raw material is converted to C5 aldehydes and finally to Cio alcohols by sequential hydroformylation, aldol condensation, and hydrogenation [268]. Union Carbide and Davy Process Technology have developed a hydro-... 

A remarkable example of the cooperation of different active sites in a polyfunctional catalyst is the one-step synthesis of 2-ethylhexanol, including a combined hydroformylation, aldol condensation, and hydrogenation process [17]. The catalyst in this case is a carbonyl-phosphine-rhodium complex immobilized on to polystyrene carrying amino groups close to the metal center. Another multistep catalytic process is the cyclooligomerization of butadiene combined with a subsequent hydroformylation or hydrogenation step [24, 25] using a styrene polymer on to which a rhodium-phosphine and a nickel-phosphine complex are anchored (cf Section 3.1.5). 

Ziegler (organoaliiminum) oxo (hydroformylation) aldol paraffin oxidation Guerbet Total ethylene, triethylaluminum olefins based on ethylene, propylene, butylene, or paraffins //-butyraldehyde paraffin hydrocarbons lower primary alcohols primary C —Clg linear alcohols primary alcohols 2-ethylhexanol secondary alcohols branched primary alcohols 0.3 4.2 a 0.2 b 4.7... 

Constructing quaternary carbon centers with adjacent functional groups is a constant goal in the total synthesis arena, especially in the synthesis of complex natural products. Furthermore, development of reactions that generate quaternary centers both stereoselectively and regioselectively are even more in demand. Keranen and Eilbracht developed a sequential enolboration/hydroformylation/aldol addition one-pot casacade sequence resulting in the formation of a cyclic ketone 57 with a new quaternary center. 

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...

In strong contrast to 1,4-diene [86], the corresponding divinylsilanes (X = Si) produce aminomethyl-substituted silacyclohexanes via a hydroformylation-aldol condensation-reductive amination pathway (Scheme 5.110) [94]. In case of R H, in the final product both substituents adopt trans geometry to each other. Such silacyclohexanes display spasmolytic and antiarthritic activity. 

Hollmann and Eilbracht [21] elucidated the intramolecular sequential hydroformylation-(aldol condensation) - hydrogenation of 3,3-dimethyl-4-penten-2-one (Scheme 5.132). The cyclization of the aldehyde formed in the first step was catalyzed by /3-toluenesulfonic acid (PTSA). The hydrogenation of the (x,P-unsaturated ketone was mediated by the same unmodified rhodium catalyst that was responsible also for the hydroformylation. 

A similar, but intermolecular version of the domino hydroformylation-(aldol condensation)-hydrogenation reaction was presented by Seller and colleagues in 2014 (Scheme 5.133) [22]. NAPHOS was used as a ligand for rhodium in the hydroformylation and in the final hydrogenation step. PyrroUdine acted as the organocatalyst. A range of terminal olefins were thus converted either with acetone or aromatic ketones into saturated product ketones. 

Scheme 5.133 Domino hydroformylation-(aldol condensation)-hydrogenation reaction with a rhodium catalyst based on NAPHOS for both hydroformylation and hydrogenation.

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