Halides, alkyl, reaction with enamines

Because of the contribution of structures such as the one on the right to the resonance hybrid, the a-carbon of an enamine is nucleophilic. However, an enamine is a much weaker nucleophile than an enolate anion. For it to react in the SN2 reaction, the alkyl halide electrophile must be very reactive (see Table 8.1). An enamine can also be used as a nucleophile in substitution reactions with acyl chlorides. The reactive electrophiles commonly used in reactions with enamines are ... 

Alkylation with simple alkyl halides is generally a poor reaction with enamines. Alkylation often takes place on nitrogen instead of carbon, and Stork and others7 have developed the aza-enolates to remedy this deficiency. A primary amine, usually cyclohexylamine, combines with an aldehyde to form an imine 42. Treatment with LDA 43 gives the lithium derivative, the analogue of a lithium enolate, known as an azaenolate 44. These intermediates are alkylated reliably at carbon 45 with most primary, and even with secondary alkyl halides, to give the alkylated aldehyde 47 after hydrolysis of the imine 46. 

With enamines of cyclic ketones direct C alkylation occurs with allyl and propargyl as well as alkyl halides. The reaction is again sensitive to the polarity of the solvent (29). The pyrrolidine enamine of cyclohexanone on reaction with ethyl iodide in dioxane gave 25% of 2-ethylcyclohexanone on hydrolysis, while in chloroform the yield was increased to 32%. 

One of the advantages of the enamine alkylation reaction over direct alkylation of the ketone under the influenee of strong base is that the major product is the monoalkylated derivative 29,32). When dialkylation is observed, it occurs at the least substituted carbon in contrast to alkylation with base, where the a-disubstituted product is formed. Dialkylation becomes the predominant reaction when a strong organic base is added and an excess of alkyl halide is used (29). Thus 1-N-pyrrolidino-l-cyclo-hexene (28) on treatment with two moles of allyl bromide in the presence of ethyl dicyclohexylamine (a strong organic base which is not alkylated under the reaction conditions) gave a 95 % yield of 2,6-diallylcyclohexanone (29). 

Reactions of Enamine Salts with OrganometalUc Compounds Organolithium and organomagnesium compounds react with enamine salts to give amines substituted on the ix-carbon atoms. The treatment of. -dehydroquinolizidinium perchlorate (163) with alkylmagnesium halides gives 9-alkylated quinolizidines (164) (252,256). Formation of... 

The formation of bicyclic imines (263,264) from piperidine enamines and y-bromopropyl amines may appear at first sight to be a simple extension of the reactions of enamines with alkyl halides. However, evidence has been found that the products are formed by an initial enamine exchange, followed by an intramolecular enamine alkylation. Thus y-bromodiethylamino-propane does not react with piperidinocyclohexene under conditions suitable for the corresponding primary amine. Furthermore, the enamine of cyclopentanone, but not that of cyclohexanone, requires a secondary rather than primary y-bromopropylamine, presumably because of the less favorable imine to enamine conversion in this instance. 

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. 

B. By Hydrolysis Reactions.—Details have appeared of the synthesis of dibenzophosphorin oxides (15) from 5-alkyldibenzophospholes, by reaction with methyl propiolate in the presence of water, and of confirmatory syntheses from phosphinic acid chlorides, as shown below. Evidence for the suggested mechanism of the ring-expansion reaction is presented. The hydrolysis of enamine phosphine oxides is an efficient, although somewhat indirect, method for the preparation of j8-ketoalkylphosphine oxides (16) [see Section 3(iii), for the preparation of enamine oxides]. Reasonable yields (48—66%) of trialkylphosphine oxides (17) have been obtained by the alkaline hydrolysis of the products from the pyrolysis at 220 °C of red phosphorus with alkyl halides, in the presence of iodine. 

Some enamine alkylation reactions are shown in Scheme 1.10. Entries 1 and 2 are typical alkylations using reactive halides. In Entries 3 and 4, the halides are secondary with a-carbonyl substituents. Entry 5 involves an unactivated primary bromide and the yield is modest. The reaction in Entry 6 involves introduction of two groups. This... 

Q Show how enols, enolate ions, and enamines act as nucleophiles. Predict the products of their reactions with halogens, alkyl halides, and other electrophiles. Show how they are useful in synthesis. 

The enamine alkylation procedure is sometimes called the Stork reaction, after its inventor, Gilbert Stork of Columbia University. The Stork reaction can alkylate or acylate the a position of a ketone, using a variety of reactive alkyl and acyl halides. Some halides that react well with enamines to give alkylated and acylated ketone derivatives are the following ... 

There is, however, a major problem with enamines reaction at nitrogen. Less reactive alkylating agents—simple alkyl halides such as methyl iodide, for example—react to a significant degree at N rather than at C. The product is a quaternary ammonium salt, which hydrolyses back to the starting material and leads to low yields. 

The best alkylating agents for silyl enol ethers are tertiary alkyl halides they form stable carbocations in the presence of Lewis acids such as TiCLj or SnCLj. Most fortunately, this is just the type of compounds that is unsuitable for reaction with lithium enolates or enamines, as elimination results rather than alkylation a nice piece of complementary selectivity. 

Draw mechanisms for the formation of this enamine, its reaction with the alkyl halide shown, and the hydrolysis of the... 

Enamines may be regarded as synthetic equivalents of enolate ions and are closely related to the enolates derived from ketones in their reactions with acyl halides, alkyl halides and a,3-unsaturated compounds. 

Nitrogen has an unshared electron pair so an enamine could function as an enolate ion. Many people had had this idea before, but nobody had done anything synthetically useful with it. We were extremely lucky because the kind of reaction we tried, the monoalkylation of a ketone enamine with an alkyl halide, is actually poor with enamines with one exception, and, by chance, it was that exception that we tried first and it worked very well. The particular molecule was a so-called -tetralon. These ketones give 90% yield by the enamine alkylation process. This was in the mid-1950s and we published a general review in 1963 [Stork, G. Brizzolara, A. H. Landesman, H. K. Szmuszkovicz, J. Terrell, R. The enamine alkylation and acylation of carbonyl compounds. /. Am. Chem. Soc. 1963,... 

The free radical chain reaction between PhCOCHjHgCl and 1-morpholinocyclohex-cne has been reported to involve addition of the acceptor radical PhCOCHj- to the jS-position of the enamine followed by electron transfer to regenerate the attacking radical (Scheme 19). Photostimulated reactions of simple alkylmercury halides failed since an electrophilic radical is required. Photolysis of p-nitrobenzyl chloride in the presence of enamines gave the -/>-nitrobenzyl ketone on hydrolysis . Radical mediated reductive alkylation of acyclic-enamines has also been reported with radical precursors such as PhSCH2CN, PhS02CH2Cl and Me3CS02CH2SePh . Reductive alkylation also occurred with chloromethyl p-tolyl sulphone in the presence of tributyltin hydride and azobis(isobutyronitrile) (AIBN) (Scheme 20). 

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