Aldehydes enolize very readily but also self-condense rather easily. Lithium enolates of aldehydes can’t be made cleanly because the self-condensation reaction happens even at –78 °C and is as fast as the enolization by LDA. Silyl enol ethers are a much better choice. They clearly must not be made via the lithium enolate, and amine bases are usually used. As each molecule of enolate is produced in the equilibrium, it is efficiently trapped by the silylating agent.

These silyl enol ethers are probably the best way of carrying out crossed aldol reactions with an aldehyde as the nucleophilic (enol or enolate) partner. An example is the reaction of the enol of the not very enolizable isobutyraldehyde with the very enolizable 3-phenylpropanal. Mixing the two aldehydes and adding base would of course lead to an orgy of self-condensa tion and cross-couplings.

Preliminary formation of the silyl enol ether from either aldehyde, in the absence of the other, would be trouble-free as Me₃SiCl captures the enolate faster than self-condensation occurs.

Here we need the silyl enol ether from isobutyraldehyde. The other aldehyde is now added along with the necessary Lewis acid, here TiCl₄. The mechanism described gives the aldol after work-up in an excellent 95% yield. No more than 5% of other reactions can have occurred.

Other useful specifi c enol equivalents of aldehydes and ketones are enamines and aza-enolates, which you saw in use in alkylation reactions. Aza-enolates—the lithium enolates of imines—derived from aldehydes are also useful in aldol reactions. Cyclohexylamine gives a reasonably stable imine even with acetaldehyde and this can be isolated and lithiated with LDA to give the aza-enolate. The mechanism is similar to the formation of lithium enolates and the lithium atom binds the nitrogen atom of the aza-enolate, just as it binds the oxygen atom of an enolate.

The aza-enolate reacts cleanly with other aldehydes or ketones to give aldol products. Even the most challenging of cross-couplings—attack on another similar enolizable aldehyde— occurs in good yield.

The initial product is a new imine, which is easily hydrolysed during acidic aqueous work up. The alkoxide is protonated, the imine hydrolysed, and finally the aldol is dehydrated to give the enal—65% overall yield in this case.

The key to the success of the aza-enolates is that the imine is first formed from the aldehyde with the primary amine, a relatively weak base, and under these conditions imine formation is faster than self-condensation. Only after the imine is formed is LDA added when self-condensation cannot occur simply because no aldehyde is left. Except in certain enamines are not generally used in aldol condensations, partly because they are not reactive enough, but mainly because they are too much in equilibrium with the carbonyl compound itself and exchange would lead to self-condensation and the wrong cross-couplings. You will see later that enamines come into their own when we want to acylate enols with the much more reactive acid chlorides.

●Aldehyde enolate equivalents For crossed aldol reactions with an aldehyde as the enol partner, use:

• silyl enol ethers or

• aza-enolates.

For acylation of aldehyde enolates (see later), use silyl enol ethers or enamines.

مواضيع ذات صلة

The Robinson annelation

Intramolecular aldol reactions

How to control aldol reactions of esters

Specifi c enol equivalents from 1,3-dicarbonyl compounds

Conjugated Wittig reagents as specific enol equivalents

Silyl enol ethers in aldol reactions

Lithium enolates in aldol reactions

The Mannich reaction

Base-promoted halogenation

Halogenation

Racemization

Thermodynamically stable enols: 1,3-dicarbonyl compounds