Enamines are the nitrogen analogues of enols and provide one solution to the aldehyde enolate problem when the electrophile is reactive. Imines are the corresponding nitrogen ana logues of aldehydes and ketones: a little lateral thinking should therefore lead you to expect some useful reactivity from the nitrogen equivalents of enolates, known as aza-enolates. Aza enolates are formed when imines are treated with LDA or other strong bases. In basic or neutral solution, imines are less electrophilic than aldehydes: they react with organolithiums, but not with many weaker nucleophiles (they are more electrophilic in acid when they are protonated). So, as the aza-enolate forms, there is no danger at all of self-condensation.

The overall sequence involves formation of the imine from the aldehyde that is to be alkylated—usually with a bulky primary amine such as t-butyl- or cyclohexylamine to dis courage even further nucleophilic attack at the imine carbon. The imine is not usually isolated, but is deprotonated directly with LDA or a Grignard reagent (these do not add to imines, but they will deprotonate them to give magnesium aza-enolates).

The resulting aza-enolate reacts like a ketone enolate with SN2-reactive alkylating agents— here, benzyl chloride—to form the new carbon–carbon bond and to re-form the imine. The alkylated imine is usually hydrolysed by the mild acidic work-up to give the alkylated aldehydes.

In the next example, a lithium base (lithium diethylamide) is used to form the aza-enolate. The ease of imine cleavage in acid is demonstrated by the selective hydrolysis to the aldehyde without any effect on the acetal introduced by the alkylation step. The product is a mono protected dialdehyde, which is difficult to prepare by other methods.

Aza-enolate alkylation is so successful that it has been extended from aldehydes, where it is essential, to ketones, where it can be a useful option. Cyclohexanones are among the most electrophilic simple ketones and can suffer from undesirable side reactions. The imine from cyclohexanone and cyclohexylamine can be deprotonated with LDA to give a lithium aza-enolate. In this example, iodomethylstannane was the alkylating agent, giving the tin-containing ketone after hydrolysis.

●Aldehyde alkylation Aza-enolates are the best general solution for alkylating aldehydes with most electrophiles. With very SN2-reactive alkylating agents, enamines can be used, and with very SN1-reactive alkylating agents, silyl enol ethers must be used.

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مواضيع ذات صلة

The Claisen ester condensation and other self-condensations

Problems with acylation at carbon

Cross-condensations

The aldol reaction

Nitroalkanes are superb nucleophiles for conjugate addition

A variety of electrophilic alkenes will accept enol(ate) nucleophiles

Conjugate addition of silyl enol ethers leads to the silyl enol ether of the product

Enamines are convenient stable enol equivalents for conjugate addition

Alkali metal (especially Na, K) enolates can undergo conjugate addition

1,3-Dicarbonyl compounds undergo conjugate addition

Using Michael acceptors as electrophiles

Conjugate addition to enones gives enolates regiospecifically