The Stork Enamine Reaction

In addition to enoiate ions, other kinds of carbon nucleophiles add to ,/ -unsaturated acceptors in the Michael reaction, greatly extending the usefulness and versatility of the process. Among the most important such nucleophiles are enamines. Recall from Section 19.9 that enamines are readily prepared by reaction between a ketone and a secondary amine  

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 carbon atom, making that carbon strongly nucleophilic. An electrostatic potential map of M,IV-dimethylaTninoethylene shows that electron density (red) is shifted toward the a position. 

Gilbert Stork (1921 - ) was born on New Year s eve in Brussels, Belgium. 

He received his secondary education in France, his undergraduate degree at the University of Florida, and his Ph.D. at the University of Wisconsin in 1945. Following a period at Harvard University, he has been Professor of Chemistry at Columbia University since 1953. A world leader in the development of organic synthesis, Stork has devised many useful new synthetic procedures. 

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, for example, an enamine adds to an a,/3-unsaturated carbonyl acceptor in a Michael-type process. The initial product is then hydrolyzed by aqueous acid (Section 19.9) to yield a 1,5-dicarbonyl compound. The overall reaction is thus a three-step sequence  

---

The Stork enamine reaction is an important and versatile method for the synthesis of a-substituted aldehydes and ketones. Such products should in principle also be... 

The Stork enamine reaction and the intramolecular aldol reaction can be carried out in sequence to allow the synthesis of cyclohexenones. For example, reaction of the pyrrolidine enamine of cyclohexanone with 3-buten-2-one. followed by enamine hydrolysis and base treatment, yields the product indicated. Write each step, and show the mechanism of each. 

Among other methods for the preparation of alkylated ketones are (1) the Stork enamine reaction (12-18), (2) the acetoacetic ester synthesis (10-104), (3) alkylation of p-keto sulfones or sulfoxides (10-104), (4) acylation of CH3SOCH2 followed by reductive cleavage (10-119), (5) treatment of a-halo ketones with lithium dialkyl-copper reagents (10-94), and (6) treatment of a-halo ketones with trialkylboranes (10-109). 

When enamines are treated with alkyl halides, an alkylation occurs that is analogous to the first step of 12-14. Hydrolysis of the imine salt gives a ketone. Since the enamine is normally formed from a ketone (16-12), the net result is alkylation of the ketone at the a position. The method, known as the Stork enamine reaction is an alternative to the ketone alkylation considered at 10-105. The Stork method has the advantage that it generally leads almost exclusively to monoalkylation of the ketone, while 10-105, when applied to ketones, is difficult to stop with the introduction of just one alkyl group. Alkylation usually takes place on the less substituted side of the original ketone. The most commonly used amines are the cyclic amines piperidine, morpholine, and pyrrolidine. 

Enamines are susceptible to acid-catalyzed hydrolysis (last step of the Stork enamine reaction) (96). Under acidic conditions, examines protonate to form the tautomeric iminium ion, which undergoes hydrolysis to the ketone as shown in Figure 57. The iminium ion undergoes hydrolysis quite readily since there is a contributing resonance form with a positive charge on the carbon (97). 

Pyrrolidine, C4H8N Reacts with ketones to yield enamines for use in the Stork enamine reaction (Sections 19.8 and 23.11). 

The Stork enamine reaction between cyclohexanone and 3-buten-2-one. Cyclohexanone is first converted into an enamine the enamine adds to the d,j -unsaturated ketone in a Michael reaction and the conjugate addition product is hydrolyzed to yield a 1,S-diketone. 

Prior to the discoveries that lithium and other less electropositive metal cations were valuable counterions for enolate alkylations, the Stork enamine reaction was introduced to overcome problems such as loss of regioselectivity and polyalkylation that plagued attempts to alkylate sodium or potassium enolates of ketones or aldehydes.Methods of synthesis of enamines by reactions of ketones and aldehydes with secondary amines have been thoroughly reviewed.Enamine alkylations are usually conducted in methanol, dioxane or acetonitrile. Enamines are ambident nucleophiles and C- and V-alkylations are usually competitive. Subsequent hydrolysis of the C-alkylated product (an iminium salt) yields an... 

The reactions that you have learned in this chapter are not just of academic interest they are critical tools that make possible the syntheses of powerful pharmaceuticals and bioactive molecules, some even on ton soale These reactions are significant because they constitute highly powerful methods for forming C—C bonds. Of the reactions you have seen thus far, though, perhaps the most versatile is the Stork enamine reaction. This general transformation was inspired by trying to copy mechanisms that nature uses for forming such C—C bonds. Since its initial discovery over half a century ago, the Stork enamine reaction has found countless applications. Here, we will mention four. 

The use of enamines as synthetic intermediates for the alkylation and acylation at the a-carbon of aldehydes and ketones was pioneered by Gilbert Stork of Columbia University. This use of enamines is called the Stork enamine reaction. 

WORKED EXAMPLE 17.9 Using the Stork Enamine Reaction... 

---