23.11 • Carbonyl Condensations with Enamines: The Stork Enamine Reaction
In addition to enolate ions, other kinds of carbon nucleophiles also add to α,β-unsaturated acceptors in Michael-like reactions. Among the most important and useful of such nucleophiles, particularly in biological chemistry, are enamines, which are readily prepared by reaction between a ketone and a secondary amine (Section 19.8). For example:
As the following resonance structures indicate, enamines are electronically similar to enolate ions. Overlap of the nitrogen lone-pair orbital with the double-bond p orbitals leads to an increase in electron density on the α carbon atom, making that carbon nucleophilic. An electrostatic potential map of N,N-dimethylaminoethylene shows this shift of electron density (red) toward the α position.
Enamines behave in much the same way as enolate ions and enter into many of the same kinds of reactions. In the Stork enamine reaction, named for its discoverer, Gilbert Stork of Columbia University, for example, an enamine adds to an α,β-unsaturated carbonyl acceptor in a Michael-like process. The initial product is then hydrolyzed by aqueous acid to yield a 1,5-dicarbonyl compound. The overall reaction is thus a three-step sequence of (1) enamine formation from a ketone, (2) Michael addition to an α,β-unsaturated carbonyl compound, and (3) enamine hydrolysis back to a ketone.
The net effect of the Stork enamine reaction is the Michael addition of a ketone to an α,β-unsaturated carbonyl compound. For example, cyclohexanone reacts with the cyclic amine pyrrolidine to yield an enamine; further reaction with an enone such as 3-buten-2-one yields a Michael adduct; and aqueous hydrolysis completes the sequence to give a 1,5-diketone (Figure 23.8).
The enamine–Michael reaction has two advantages over the enolate-ion–Michael reaction that makes it particularly useful in biological pathways. First, an enamine is neutral, easily prepared, and easily handled, while an enolate ion is charged, sometimes difficult to prepare, and must be handled carefully. Second, an enamine from a monoketone can be used in the Michael addition, whereas only enolate ions from β-dicarbonyl compounds can be used.
Using the Stork Enamine Reaction
How might you use an enamine reaction to prepare the following compound?