Stork-Enamine ketones

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... 

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. 

Stork enamine synthesis takes advantage of the fact that an aldehyde or ketone reacts with a secondciry cimine to produce an enamine. Enamines cire resonance stabilized (see Figure 15-25) and have multiple applications. In the first resonance structure, the nitrogen is the nucleophile, while in the second resonance structure, the Ccirbanion is the nucleophile. Some commonly used secondary amines, pyrrolidine, piperidine, and morpholine, are shown in Figure 15-26. 

Stork Enamine Reaction Aldehydes and ketones react with secondary amines to form compounds called enamines. The general reaction for enamine formation can be written as... 

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 first examples of a Michael-Stork enamine addition to allenyl esters and ketones R1CH=C=C(R2)COX (X = alkyl, alkoxyl) has been reported. Mechanistic investigation revealed that 2 equiv. of enamine are required for optimum yields. In the case of an allenyl methyl ketone, cyclopentyl enamine addition afforded 8-oxobicyclo[3.2.1]octane, providing evidence for the in situ formation of an enamine intermediate following the initial Michael-Stork reaction.187... 

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

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. 

The net effect of the Stork enamine sequence is the Michael addition of a ketone to an o, unsaturatcd cprbonyl compound. For example, cyclohexanone reacts with the cyclic amine pyrrolidine to yield an enamine fuj-ther reaction with an enone ssich as 3-buten-2 One yields a Michaahtyi>e adduct and aqueous hydrolysie completes the sequence to provide a l/> diketone product (Figure 23.8>. 

Enamines like enolates are alkylated when treated with reactive alkylating agent, a-Substituted enamines can be converted into aldehydes and ketones by acid-catalyzed hydrolysis. Thus, in the three-step process, alkylation of aldehydes and ketones may be carried out via enamines (Stork enamine synthesis) (Scheme 3.19). 

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. 

Stork enamine synthesis Alkylation of enamines with alkyl halides to afford a-alkylated aldehydes or ketones. 444... 

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... 

This method has been extended by Stork and his group to many ketones and a large number of applications may be found in the literature " . According to the procedure outlined by Stork, a ketone (1 equivalent), an amine (1.5-2 equivalents) and a catalytic amount of p-toluenesulphonic acid were refluxed in toluene under a Dean-Stark water trap. About 400 ml of solvent and 2 g of the catalysing acid were used per mole of ketone. The construction of a simple and inexpensive water separator for the preparation of the pyrrolidine enamine of cyclohexanone in the student organic laboratory was described. The azeotropic procedure has also been employed using one equivalent of amine with and without solvent to give the enamine directly. Various techniques in addition to azeotropic removal of water have been used to drive the enamine formation to completion, as well as to accelerate the rate of its formation. 

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. 

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. 

This strategy will not work, because it involves the use of an enolate, which is not an efficient Michael donor. Therefore, we consider a Stork enamine synthesis (in which we use an enamine, rather than an enolate, as a Michael donor). The enamine can be made from the starting ketone upon treatment with a secondary amine under acid-catalyzed conditions (with removal of water) ... 

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. 

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). 

This innovation was exploited by Stork and his co-workers (6-8) for a study of enamine formation from a variety of ketones and secondary amines. 

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. 

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