Enamines as Enolate Anion Surrogates

The formation of enamines by reaction of 2º-amines with aldehydes or ketones has been described. The double bond of the enamine transmits the nucleophilic character of the nitrogen to the alpha-carbon, in a vinylagous fashion. Because of the resulting ambident nucleophilicity of the enamines, reactions with electrophiles may take place at either nitrogen or carbon. Enamines derived from aldehydes are usually alkylated on nitrogen, an undesirable course for most synthetic applications. Ketones give significant C-alkylation, the thermodynamically favored course, as first demonstrated by G. Stork (Columbia). The iminium ion created by C-alkylation cannot react further, and is easily hydrolyzed to the alkylated ketone. This is particularly useful if dialkylation products are to be avoided. Thus, in the first example, direct methylation of the enolate anion from this ketone gives significant amounts of the dimethyl product, due to enolate proton exchange. As shown, the enamine route gives only mono-methylated product.
The second example demonstrates that enamines may be acylated as well as alkylated. In fact, the reversible nature of acylation removes the problem of competing N-acylation. This case also illustrates the general tendency to form the least substituted enamine when two different alpha-sites are present. Conjugation of the non-bonding electron pair on nitrogen with the pi-electrons of the double bond forces the alkyl substituents on nitrogen to lie in the same plane as the double bond (see the resonance equation displayed by the "Toggle Mechanism" button). As a result substitution of the double bond leads to increased steric hindrance with the nitrogen substituents. The five-membered cyclic 2º-amine pyrrolidine is widely used for enamine reactions, in part because this steric hindrance is minimized.