Condensation Reactions of Enols and Enolates

The ideal approach for the preparation of conjugated carbonyl compounds having an exo-methylene group would be via a mixed aldol condensation of an enolizable carbonyl substrate with formaldehyde as the electrophilic partner. However, formaldehyde is a very powerful electrophile and tends to react more than once with enols and enolates. This shortcoming can be circumvented by converting the formaldehyde to an iminium ion (Mannich reagent) by reaction with a secondary amine, usually dimethy-lamine, and a catalytic amount of HCl. 

In the presence of an enolizable aldehyde or a ketone, the resultant electrophilic iminium ion reacts in situ with the enol to produce, after neutralization, the corresponding (3-amino ketone, also called a Mannich base. Unsymmetrically substituted ketones are aminomethylated preferentially at the more highly substituted carbon of the enol. 

Utilization of preprepai ed A,A-dimethylmethyleneammonium iodide (Eschenmoser salt) or chloride gives higher yields of (3-amino ketones than does the classical Mannich reaction. Silyl enol ethers also react with the Eschenmoser salt to give Mannich bases, as exemplified below. 

In addition to the Mannich reaction being a valuable method for preparing amino ketones,which are encountered in many drugs, the reaction is also important in organic synthesis in providing a stable equivalent of a conjugated exo-methylene moiety. Thus, addition of methyl iodide to the Mannich base converts it to the quaternary ammonium salt. Subsequent treatment with a base results in a [3-elimination of trimethylamine to generate the a-methylene ketone. 

Aminomethylation of lactone enolates with the Eschenmoser salt followed by neutralization (workup) yields the corresponding Mannich bases. Their conversion to quaternary ammonium iodides followed by treatment with DBU (1,5-diazabicy-clo[5.4.0]undec-5-ene) leads to a-methylene lactones. 

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