Crossed aldol condensation successful

A possible mechanism for the P-alkylation of secondary alcohols with primary alcohols catalyzed by a 1/base system is illustrated in Scheme 5.28. The first step of the reaction involves oxidation of the primary and secondary alcohols to aldehydes and ketones, accompanied by the transitory generation of a hydrido iridium species. A base-mediated cross-aldol condensation then occurs to give an a,P-unsaturated ketone. Finally, successive transfer hydrogenation of the C=C and C=0 double bonds of the a,P-unsaturated ketone by the hydrido iridium species occurs to give the product. 

If die enolate nucleophile is derived from an aldehyde or ketone different than die carbonyl electrophile, a crossed-aldol condensation results. Normally best success is achieved if the carbonyl electrophile employed for the crossed-aldol condensation is more reactive than the carbonyl electrophile from which the enolate is derived. For example, ketone etiolates react with aldehydes effectively, but aldehyde enolates do not give the crossed aldol with most ketones but self-condense instead. 

The following two reactions are successful crossed aldol condensations. The aldol products may or may not undergo dehydration, depending on the reaction conditions and the structure of the products. 

The stereochemical course of several Co2(CO)6-mediated reactions has been studied. For example, although alkynyl aldehydes undergo crossed aldol condensation with trimethylsilyl enol ethers with little stereoselectivity, their hexacarbonyldicobalt derivatives react with moderate to excellent syn diastereoselectivity.96 101 The mechanism behind this selectivity has not been fully elucidated and is complicated by the lluxional nature of the intermediate cations. This stereoselective reaction has been successfully applied to the synthesis of /3-lactam antibiotics.100... 

The choice of an aldehyde such as 2-methylpropanal (26) having only one a-hydrogen atom is important to the success of this crossed-aldol condensation because its dimerization is of no consequence. For example, aldehyde 26 can readily react with another molecule of itself to give 35 (Eq. 18.13), but this process is reversible under the reaction conditions. Moreover, unlike the aldol product 34,35 is incapable of dehydrating to give an a,p-unsaturated product and water, which would drive the equilibrium leading to the dimerization product. It is left to you to consider the possibility of self-condensation of 3-buten-2-one (27) and of the reaction of enol 30 with the carbon atom of the protonated carbonyl function in 31 (see Exercises 12 and 13 at the end of this section). 

This crossed aldol reaction between acetone and an aldehyde may be carried out successfully by treating acetone with one equivalent of LDA to convert it completely to its enolate anion. The preformed enolate is then treated with the aldehyde followed by workup in water to give the crossed aldol condensation product. 

As in the crossed aldol condensation, there are some simple steps we can take to improve matters. If one of the starting esters has no a hydrogen, there can be no eno-late formation from it, and it can act only as an electrophile, never as a nucleophile. It is helpful to add the ester wth an a hydrogen to a mixture of the partner without an a hydrogen and the base. As the enolate is formed it is more likely to react with the ester that has no a hydrogen since it is present in excess. Using this technique, a successful crossed Claisen can be achieved. Benzoates, formates, and carbonates are examples of esters without a hydrogens and are often used (Fig. 19.109). 

Polyacetal resins have a repeating unit of -O-CH2-. They are strong, stiff polymers for valves, hoses, and tube connectors. Pentaerythritol finds end-uses in alkyd resins and explosives (pentaerythritol tetranitrate). To appreciate this synthesis, the student should review two condensation reactions, the crossed aldol and the crossed Cannizzaro. Acetaldehyde reacts with 3 mol of formaldehyde in three successive aldol condensations. This product then undergoes a Cannizzaro reaction with formaldehyde. 

Among the enolates of carboxylic acid derivatives, esters are the most widely used. Ester enolates cannot be used in crossed aldols with aldehydes because the aldehyde is both more enolizable and more electrophilic than the ester. It will just condense with itself and ignore the ester. The same is true for ketones. A specific enol equivalent for the ester will therefore be needed for a successful ester aldol reaction. 

Aldol condensation. Japanese investigators report that trimethylsilyl enol ethers of aldehydes or ketones react with carbonyl compounds in the presence of an equimolar amount of titanium tetrachloride to give the cross-aldol products in satisfactory yields. The success of the method probably depends on formation of an intermediate titanium chelate ... 

In contrast the reaction of a 1 1 molar mixture of i50-butanal and n-butanal ran successfully for 20 hours with no gross carbon laydown on the discharged catalyst (3.1 wt%). The products formed were 2-ethyl hexenal as expected from the self-condensation reaction of n-butanal and 2-ethyl-4-methyl-pent-2-enal, the dehydrated product from the crossed aldol reaction of n and /50-butanal (Table 6). The overall selectivity of this reaction to aldol products is lower than the selectivties achieved with crushed 4 wt %... 

We developed powerfiil Ti- or Zr-Claisen condensation between esters and direct crossed Ti-aldol addition between ketones and ketones or aldehydes. These reactions were successfully applied to the short and practical method for synthesizing some natural macrocyclic musks (civetone and muscone), mints (mintlactone and menthofuran), and a jasmine perfume. 

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