Enamine Stork reaction

Enamines 1 are useful intermediates in organic synthesis. Their use for the synthesis of a-substituted aldehydes or ketones 3 by reaction with an electrophilic reactant—e.g. an alkyl halide 2, an acyl halide or an acceptor-substituted alkene—is named after Gilbert Stork. 

The typical reactivity of an enamine 1 results from the nucleophilic character of the /3-carbon center, as indicated by a resonance structure  

An enamine is easily prepared by reaction of the corresponding aldehyde or ketone 4 and a secondary amine 5. A cyclic secondary amine like pyrrolidine, piperidine or morpholine is most often used. A general procedure has been reported by Mannich and Davidseti in 1936  

In order to shift the equilibrium, the water formed in that reaction is usually removed by azeotropic distillation with benzene or toluene. 

In general the Stork reaction gives moderate yields with simple alkyl halides better yields of alkylated product are obtained with more electrophilic reactants such like allylic, benzylic or propargylic halides or an a-halo ether, a-halo ester or a-halo ketone. An example is the reaction of 1-pyrrolidino-l-cyclohexene 6 with allyl bromide, followed by aqueous acidic workup, to yield 2-allylcyclohexanone  

A variant of the Robinson annulation, where bulky amines such as pyrrolidine are used, making the conjugate addition to MVK take place at the less hindered side of two possible enamines. 

Enamines Synthesis, Structure, and Reactions Cook, A. G., Ed. Dekker New York, 1969, 514. (Review). 

Terrell, R. Szmuszkovicz, J. J. Am. Chem. Soc. 1954, 76, 2029. Gilbert J. Stork (1921-) was born in Brussels, Belgium. Being Jewish, he immigrated to the US due to rising antisemitism. He earned his Ph.D. at Wisconsin in 1945 and later became an assistant professor at Harvard. Since he was not awarded tenure in 1953, Stork moved to Columbia University where he has taught ever since. 

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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. 

How could you prepare the following cvclohexenones by combining a Stork enamine reaction with an intramolecular aldol condensation (See Problem 23.53.)... 

Sandmeyer reaction, 943 saponification. 809-810 SN1 reaction, 373-375 Sn2 reaction, 363-364 Stork enamine reaction, 897-898 transamination, 1167 Williamson ether synthesis, 655 Wittig reaction, 720-721 Wolff-Kishner reaction, 715-716 Meerwein-Ponndorf-Verley reaction, 746... 

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. 

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],... 

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... 

Spiroannelation Boron trifluoride etherate, 43 Triphenyltin hydride, 335 Stork-enamine reaction (see Alkylation reactions)... 

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). 

Michael donor Stork enamine reaction Robinson annulation reaction... 

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. 

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 ... 

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