Enamines, reaction with halides

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%. 

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). 

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. 

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. 

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. 

The enamine 141 can be cyclized to the [l,2,4]triazolopyridopyrimidine 142 upon treatment with sodium ethoxide (Scheme 40) <2002M1297>. This fused tricyclic system may also be obtained, like the pteridine analogue (cf. Scheme 38), from the reaction of hydrazonoyl halides and pyridopyrimidines such as 143, and also by treatment of the triazolopyrimidine 144 with dimethylformamide dimethylacetal (DMF-DMA) dimethylacetal and subsequent ring closure <2003MOL333, 2003HAC491> (Scheme 41). Another series of triazolopyridopyrimidines, for example, 146, can be prepared from a hydrazine-substituted pyridopyrimidine 145, in two ways either directly by reaction with an acid chloride, or via a derived hydrazone (Scheme 42) <1996MI585>. 

The reactions of enamines (516) with trialkylsilyl halides in the presence of triethylamine (or other nitrogen bases) produce 3-halomethyl-substituted oxazines (517) (or 517 ) in good yields (Scheme 3.268) (472). 

Stork Enamine Synthesis A reaction leading to the formation of an a-alkyl or a-carbonyl compound from an alkyl or aryl halide reacting with an enamine. 

The reactions of tertiary allylic amines with vinylic halides are related closely to the allylic alcohol reactions since enamines are often major products. We have just begun work in this area and have few results to report yet. We have seen some significant differences in the products formed from tertiary allylic amines and from the related allylic alcohols. A typical example is the reaction of 2-bromopropene with N-allyl piperidine and piperdine where a 42% yield of a single enamine is obtained (6). The related reaction with allyl alcohol gives a mixture of regioisomeric enamines. 

The scope of this reaction appeared to be limited to dialkylamides and electron-neutral aryl halides. For example, nitro-, acyl-, methoxy-, and dimethylamino-substituted aryl halides gave poor yields upon palladium-catalyzed reaction with tributyltin diethylamide. Further, aryl bromides were the only aryl halides to give any reaction product. Vinyl bromides gave modest yields of enamines in some cases. Only unhindered dialkyl tin amides gave substantial amounts of amination product. The mechanism did not appear to involve radicals or benzyne intermediates. 

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... 

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