Enamines with alkyl halides

A large number of cyclopropanes have been synthesized from cyclopropyl sulfones, cyclopropyl sulfoxides and cyclopropyl sulfides by taking advantage of the acidity of the cyclopropyl proton a to the C-S bond. Butyllithium is used almost exclusively as the base. The cyclopropyl anions obtained are capable of reacting with alkyl halides, aldehydes, enamines, epoxides, esters. 

Alkylations of enamines of a,)9-unsaturated ketones with alkyl halides often give very poor yields of C-alkylated products because of competing. -alkylation.In the type of transformation illustrated here, direct alkylations of enamines are completely unsuccessful, even in cases where hindered enamines are used. On the other hand, the metaUoenamine method can be applied generally with good success in the problem of monoalkylation of ,)3-unsaturated ketones. ... 

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). 

Stereochemical positioning of a functional group, relative to a separate enamine moiety in the same molecule, can be done in such a manner that a simple intramolecular alkylation or acylation will cause cyclization. Such intramolecular cycloalkylations with alkyl halides have been reported 107,108). Inftamolecular cycloacylations of enamines with esters 109, 110,110a) and with nitriles 110a,l 11,111a) have also been observed. 

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... 

In the alkylation of enolate anions, a mixture of mono- and polyalky lation produets is usually obtained, and when enolization of a di-a-methylene ketone is possible toward both sides, a mixture of di-a- and a,a -dialkylation products ean be expeeted. Thus the enamine alkylation sequenee beeomes partieularly attractive when eontrolled monoalkylation is imperative beeause of difficulties in separation of a mixture of alkylation produets. One of its first synthetie applications was in the reaetions of /8-tetralones with alkyl halides. Yields in exeess of 80% were usually found 238-243) in these reaetions, which make valuable intermediates for steroid and diterpene syntheses more aecessible. 

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. 

A fundamental problem in the alkylation of enamines, which is inherent in the bidentate system, is the competition between the desired carbon alkylation and attack at the nitrogen. With unactivated alkyl halides (3,267), this becomes especially serious with the enamines derived fromcycloheptan-one, cyclooctanone, cyclononanone, and enamines derived from aldehydes. Increasing amounts of carbon alkylation are found with the more reactive allyl and benzyl halides (268-273). However, with allyl halides one also observes increasing amounts of dialkylation of enamines. 

The problem of nitrogen alkylation of enamines, which one encounters with alkyl halides, is of no consequence in alkylations with positively activated olefins, since the generation of amonium salts can be expected to be reversible in these cases. Thus such enamine alkylations are obviously attractive to the synthetic chemist. Their particular importance, however, arises from avoidance of the serious obstacles often found with parallel enolate anion reactions. 

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 jS-position of enamines is highly nucleophilic and may react with alkyl halides, acyl chlorides or anhydrides, or with Michael addition substrates to give carbon-carbon bonds as shown in the examples (1). 

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. 

Primary and secondary halides do not perform well, mostly because N-alkylation becomes important, particularly with enamines derived from aldehydes. An alternative method, which gives good yields of alkylation with primary and secondary halides, is alkylation of enamine salts, which are prepared by treating an imine with ethylmagnesium bromide in THF ... 

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. 

Just as enamines are more nucleophilic than enol ethers, imine anions are more nucleophilic than enolates and react efficiently with alkyl halides. One application of imine anions is for the alkylation of aldehydes. 

Tin-based reagents are not always snitable owing to the toxicity of organotin derivatives and the difficulties often encountered in removing tin residues from the final product. Therefore, the same authors have carried out additional experiments with 17d and several different alkyl halides under tin-free conditions. The treatment of 16d with tert-butyldiphenylsilyl chloride (TBDPSCl) and triethylamine in the presence of silver triflate in CH2CI2 affords the bis(silyloxy)enamine 17d in 92% yield (Scheme 17). When the radical reaction was carried out with ethyl iodoacetate in the presence of 2,2 -azobis(4-methoxy-2,4-dimethylvaleronitrile) (V-70) as the initiator in CH2CI2, the oxime ether 19 was obtained in 83% yield (Scheme 17). 

Alkylation of enamines may lead to the formation of N-alkylated product, which on heating is converted to C-alkyl compound (This rearrangement is common with allylic halide, alkyl halide or a-haloacetic ester. 

The alkylation of caclohexanone has been studied as a model reaction in detail. Generally, enamino compounds (126) are allowed to react with alkyl halides or a, 3-unsaturated carbonyl compounds. The enamine (126a) is prepared directly from the ketone and a chiral secondary amine (route A). A metalloenamine (126b) can be synthesized from chiral azomethine, derived from the model ketone and a primary chiral amine (route B). The primary amine used for the formation of (126b) must possess an oxygen function. This oxygen function plays a key role in the coordination of the lithium ion in the complex (126b). 

Simple alkylation of the chiral chelate complex leads to formation of chiral dialkylacetic acids (Scheme 109).3S5 388 Simpler chiral enamines can also be used. The formation of chiral propanoic acids results from a resolution of racemic alkyl halides by the interaction of a chiral lithiooxazoline, which recognizes and reacts with one enantiomer at the expense of the other (Scheme 110).389 The above aspects of the asymmetric carbon—carbon bond formation from chiral oxazolines have been reviewed by Meyers.390... 

The enamines prepared from acetaldehyde or monosubstituted acetaldehydes undergo self-condensation in the reaction mixture very readily so that alkylation is practically impossible. Enamines prepared from disubstituted aldehydes are exclusively iV-alkylated on treatment with aliphatic alkyl halides,218 whereas allyl halides cause... 

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 ... 

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. 

Enamines are intermediate in reactivity more reactive than an enol, but less reactive than an enolate ion. Enamine reactions occur under milder conditions than enolate reactions, so they avoid many side reactions. Enamines displace halides from reactive alkyl halides, giving alkylated iminium salts. The iminium ions are unreactive toward further alkylation or acylation. The following example shows benzyl bromide reacting with the pyrrolidine enamine of cyclohexanone. 

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. 

Enamines are among the most powerful neutral nucleophiles and react spontaneously with alkyl halides. Silyl enol ethers are less reactive and so require a more potent electrophile to initiate reaction. Carbocations will do, and they can be generated in situ by abstraction of a halide or other leaving group from a saturated carbon centre by a Lewis acid. 

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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