Enamines with acyl halides

The treatment of enamines with acid halides which possess no a hydrogens results in the simple acylation of the enamine (7,12,62-67). If the acid halide possesses an a hydrogen, however, ketenes are produced in situ through base-catalyzed elimination of hydrogen chloride from the acid halide. The base catalyst for this reaction may be the enamine itself or some other base introduced into the reaction mixture such as triethylamine. However, if the ketene is produced in situ instead of externally, there still remains the possibility of a side reaction between the acid halide and the enamine other than the production of ketene (67,84). 

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 reaction of enamines with ketenes can be conveniently carried out by generating the ketene in situ from an acyl halide and a tertiary amine. 

C(R)=NR group with a nitrilium salt RCssNR .222 The acylation of the enamine can take place by the same mechanism as alkylation, but another mechanism is also possible, if the acyl halide has an a hydrogen and if a tertiary amine is present, as it often is (it is added to neutralize the HX given off). In this mechanism, the acyl halide is dehydrohalogenated by the tertiary amine, producing a ketene (7-14) which adds to the enamine to give a cyclobutanone (5-49). This compound can be cleaved in the solution to form the same acylated imine salt (27) that would form by the more direct mechanism, or it can be isolated (in the case of enamines derived from aldehydes), or it may cleave in other ways.223... 

Pyridine /V-oxides in the presence of acyl halides react with enamines and indoles as shown (Scheme 28). 

The monoarylated enamine can then be acylated to form a mixture of 2-acyl-2-arylcyclohexanone and 2-aryl-6-acylcyclohexanone. This was held to indicate that arylation affords two enamines, 62 and 63, which differ only in the position of the double bond. The reaction involving acyl halides could be explained under the assumption that in the more probable enamine structure (with conjugation through the free electron pair on nitrogen, the double bond, and the aromatic ring) it is the hydrogen atom on C(6) which is more acidic. 

From a preparative point of view, the acylation of ketones via enamines is of particular interest. In comparison with pyrrolidine and piperidine enamines, the less reactive morpholine enamines give better yields, as found by Hiinig et al.2iZ j8-Diketones are the products of acylation with an acyl halide followed by acid hydrolysis, whereas with ethyl chloroformate, /J-ketoesters are obtained.212 Hiinig and his collaborators242-247 have used the acylation of 1-morpholino-l-cyclopentene and 1-morpholino-l-cyclohexene to lengthen the chains of acids by five and six carbon atoms, respectively. The reaction may... 

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 ... 

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 ... 

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. 

Amides are converted to enamines by reaction with the Tebbe reagent (equation 24), whereas acyl halides lead to enolates (equation 25). Anhydrides lead to a combination of enolate formation, methyl-enation and enolization. ... 

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,... 

Acylation A useful method for preparing 1,3-diketones and -keto esters from ketones is to first form the enamine and then acylate it with an appropriate acyl chloride derivative. Morpholine, a 5ec-amine, is a good choice for this purpose since the derived enamines have lower reactivity toward acyl halides, allowing for more control of the reaction. 

When an enamine reacts with an acyl halide or acid anyhydrides the product is the C-acylated compound. The iminium ion that forms hydrolyzes when water is added, and overall reaction provides a synthesis of P-diketones. 

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