Chapter 22, Problem 60DSP

Synthetic Applications of Enamines

The formation of enamines by the reaction of aldehydes and ketones with secondary amines was

described in Section $\text{18}\text{.11}$. As the following equation illustrates, the reaction is reversible.

When preparing enamines, the reaction is normally carried out by heating in benzene as the solvent. No catalyst is necessary, but $\text{p-toluenesulfonic acid}$ is sometimes added. The water formed is removed by distillation of its azeotropic mixture with benzene, which shifts the position of equilibrium to the right to give the enamine in high yield. Conversely, enamines can be hydrolyzed in aqueous acid to aldehydes and ketones.

Enamines resemble enols in that electron-pair donation makes their double bond electron-rich

and nucleophilic.

Because nitrogen is a better electron-pair donor than oxygen, an enamine is more nucleophilic thanan enol. Enamines, being neutral molecules, are, however, less nucleophilic than enolates, which areanions.

Reactions of enamines with electrophiles $\left({\text{E}}^{\text{+}}\right)$ lead to carbon–carbon bond formation. Sub sequent hydrolysis gives an $\text{α-substituted}$ derivative of the original aldehyde or ketone.

Pyrrolidine is the secondary amine used most often for making enamines from aldehydes and

ketones.

For synthetic purposes, the electrophilic reagents that give the best yields of $\text{α-substituted aldehydes}$ and ketones on reactions with enamines are the following:

Alkyl halides that are very reactive in ${\text{SN}}_{\text{2}}$ reactions such as primary allylic and benzylic halides, $\text{α-halo}$ ethers $\text{α-halo esters}$, and $\text{α-halo nitriles}\text{.}$

Acyl chlorides and acid anhydrides.

Michael acceptors: $\text{α,β-unsaturated nitriles}$, esters, and ketones.

$\text{22}\text{.60}$ $\left(\text{+}\right)\text{-2-Allylcyclohexanone}$ has been prepared in $\text{82\%}$ enantiomeric excess by alkylation of the optically active enamine prepared from cyclohexanone and an enantiomerically pure

pyrrolidine derivative. Of the following, which one is the best pyrrolidine derivative to use

in this enantioselective synthesis?