In the Stork enamine reaction

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 ... 

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). 

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. 

OS 73] [R 4a] [P 54] The micro reactor yield (up to 42%) is comparable to that for batch Stork-enamine reactions using p-toluenesulfonic acid in methanol imder Dean and Stark conditions [11],... 

As pointed out by Stork and coworkers in their definitive 1963 paper3, the reaction with electrophilic alkenes is especially successful since reaction at nitrogen is reversible. Reaction at the /2-carbon is (usually) rendered irreversible by, in the case of cyclohexanone enamines, internal proton transfer of the axial C-/2 proton to the anionic centre of the initially formed zwitterionic intermediate (34), under conditions of stereoelectronic control (Scheme 22). When this intramolecular proton transfer cannot occur in aprotic solvents, or when the product produced in protic solvents is a stronger carbon acid than adduct 35 (i.e. when Z = COR, N02), then carbon alkylation is also reversible and surprising changes in the regioselectivity of reaction may be observed (vide infra see also Section VI.D and Chapter 26). Cyclobutanes (36) and, in the case of a,/ -unsaturated... 

Stork enamine reaction (Section 23.11) a multistep sequence whereby a ketone is converted into an enamine by treatment with a secondary amine, and the enamine is then used in Michael reactions. 

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. ... 

Stork enamine reaction The reaction of an enamine with an alkyl halide that results in the alkylation of the (P-carbon. Usually followed by hydrolysis of the resultant imine salt to give a carbonyl functionality at the a-carbon. 

Enamines can be used in place of enolates in Michael reactions. When an enamine is used as a nucleophile in a Michael reaction, the reaction is called a Stork enamine reaction. 

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. 

The nucieophiiicity of the carbon of enamines makes them particularly useful reagents in organic synthesis because they can be acylated, alkylated, and used in Michael additions (see Section 19.7A). Enamines can be used as synthetic equivalents of aldehyde or ketone enolates because the alkene carbon of an enamine reacts the same way as does the a carbon of an aldehyde or ketone enolate and, after hydrolysis, the products are the same. Development of these techniques originated with the work of Gilbert Stork of Columbia University, and in his honor they have come to be known as Stork enamine reactions. 

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. 

Stork enamine reaction uses an enamine as a nucleophile in a Michael reaction, straight-chain alkane (normal alkane) an alkane in which the carbons form a continuous chain with no branches. 

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). 

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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