In the Stork enamine

Some secondary amines commonly used in the Stork enamine synthesis. 

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

Enuminua behave in much the name way aa enolaU ion und enter into many oTthe eame kinds of reactions. In the Stork enamine reaction, for example, an enamine adds to an ar, i unaaturated carbonyl acceptor in a Michael-type process. Theinilial product is than hydrolyzed by aqueouB acid (Section 1. 9) to yield a UMicarbonyl compound. The overall reaction i thua a three-atep sequence ... 

In the Stork enamine synthesis, the pyrrolidine acts as a sacrificial reagent to electronically facilitate the alpha-carbon alkylation. The formation of the enamine is 100% atom economical. 

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. 

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). 

When the nitrogen of the substrate contains a chiral R group, both the Stork enamine synthesis and the enamine salt method can be used to perform enantiose-lective syntheses. The use of A-proline can generate a chiral enamine in situ, thus allowing alkylation to occur, giving alkylated product with good enantioselec-tivity,. The reaction has been done intramolecularly. ... 

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. 

In this chapter, we have seen many reactions that form C—C bonds. Three of those reactions are worth special attention, because of their abiUty to produce compounds with two functional groups. The aldol addition, the Claisen condensation, and the Stork enamine synthesis all produce difunctionahzed compounds, yet they differ from each other in the ultimate positioning of the functional groups. The Stork enamine synthesis produces 1,5 difunctionalized compounds. 

In the end, we prepared the desired product. This synthetic strategy is called the Stork enamine synthesis, and it can come in handy when you are proposing syntheses. Whenever you are trying to propose a synthesis, and you decide that you need an enolate to attack as a nucleophile in a 1,4-addition, you will have a problem. Regular enolates are not stable enough to be Michael donors. But, you can convert it into an enamine, which is stable enough to be a Michael donor. Then, you can remove the enamine in the end. The enamine serves as a way of temporarily modifying the reactivity of the enolate so that we can achieve the desired result. It is very clever when you really think about it. 

Enamines behave in mnch the same way as enolate ions and enter into many of the same kinds of reactions. In the Stork reaction, for example, an enamine adds to an a,/3-unsatnrated carhonyl acceptor in a Michael-like process. The initial product is then hydrolyzed hy aqueous acid (Section 14.7) 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 a,j8-unsaturated carbonyl compound, and (3) enamine hydrolysis back to a ketone. 

In 1954 Stork et al. (i) reported that the alkylation of the pyrrolidine enamine of cyclohexanone (5) with methyl iodide followed by acid hydro-I ysis led to the monoalkylated ketone. It was thus obvious that the enamine (7) derived by the loss of proton from the intermediate methylated iminium cation (6) failed to undergo any further alkylation. 

In their original communication on the alkylation and acylation of enamines, Stork et al. (3) had reported that the pyrrolidine enamine of cyclohexanone underwent monoacylation with acid chlorides. For example, the acylation with benzoyl chloride led to monobenzoylcyclohexanone. However, Hunig and Lendle (33) found that treatment of the morpholine enamine of cyclopentanone with 2 moles of propionyl chloride followed by acid hydrolysis gave the enol ester (56), which was proposed to have arisen from the intermediate (55). 

Anotheranalogy between the enolate anions derived from a,)3-unsatura ted ketones and the corresponding enamines is encountered in their alkylation reactions (57), which proceed by the kinetically controlled attack at the a-carbon atom. For instance, Stork and Birnbaum (51) found that the alkylation of the morpholine enamine of /J -octalone-2 (117) with methyl iodide gave the C-1 methylated derivative (118). 

The magnitude of the preference for the formation of the less substituted enamine from unsymmetrical ketones as expressed by the general rule given above is not entirely clear. House and Schellenbaum 48) have reported that 2-methylcyclohexanone and pyrrolidine produce a product mixture of tetra- and trisubstituted enamines in a ratio of 15 85. The estimate of this ratio was made from NMR data. In contrast Stork and co-workers (9) report the formation of 100% trisubstituted enamine as determined by NMR spectroscopy. 

A novel ring closure was discovered by Stork (6) in which the pyrrolidine enamine of a cycloalkanone reacts with acrolein. The scheme illustrates the sequence in the case of 1-pyrrolidino-l-cyclohexene, and the cyclopentane compound was found to undergo the reaction analogously. The procedure details the preparation of the bicyclo adduct and its cleavage to 4-cyclooctenecarboxylic acid. 

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