Allylic halides, reaction with enamines

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. 

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%. 

A two-step cyclization of an enamine with an electrophilic olefin has been reported in which the first step is alkylation by an allyl halide and the second step is alkylation by the electrophilic olefin (50). The reaction... 

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... 

Enamines are inclined to react at nitrogen with alkyl halides, but react particularly well with a-halo carbonyl compounds 58 to give 1,4-dicarbonyl products 60, and with allylic halides by reaction at nitrogen followed by a [3,3] sigmatropic rearrangement 61 to give y,8-unsaturated... 

The allylation of ketones is a simple reaction. Most of the specific enol equivalents described in chapters 2-6 react well with allylic halides. Disconnection of the y,5-unsaturated ketone 59 to the enolate 61 and the allylic halide 60 is trivial and the reaction of, say, an enamine will occur at the less hindered primary centre to give 59. However, supposing the target molecule is the isomeric ketone 63. The same disconnection gives the isomeric allylic bromide 62 which will almost certainly give the alternative product 59 by reaction at the less hindered end of the alkene. 

In 2011, Palomo [114] reported the first enamine-mediated direct asymmetric a-alkylation of aldehydes with electron-deficient allylic halides, in which the key C—C bond-formation proceeds via an 8 2 pathway. The reaction is efficiently catalyzed by co-catalysts system diphenylprolinol derivative/DMAP or DABCO... 

The reactions of enamines with electrophiles follow a similar course and are also of OE t type. Enamines are isoconjugate with enolate ions and can likewise react with electrophiles in two different ways, either on nitrogen to form an enammonium ion or on carbon to form a methyleneammonium ion. As in the case of enolate ions, protonation takes place more rapidly on the heteroatom (here nitrogen) rather than carbon while allyl halides, e.g., methyl iodide, give C-alkylated products e.g.. 

Allylic amines are coupled to halides giving either allylic amines or enamines depending on the reaction condition. Reaction of steroidal dienyl triflate with Boc-diprotected allylamine affords allylamine. Use of AcOK as a base is crucial for the clean coupling[102]. The tert-allylic amine 123 reacts with an aryl halide to give the enamine 125 in DMF and allylic amine 124 in nonpolar solvents[103]. 

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). 

Activated olefins (acrylonitrile, methyl acrylate), and halides such as allyl bromide and ethyl bromoacetate were used as electrophiles. In nonpolar solvents, the enamines (126a) were alkylated with high enantioselectivity, but poor chemical yields. In polar solvents, the chemical yields were acceptable, the optical yields poor 148). A similar reaction sequence has been used successfully for the synthesis of (+)-mesembrine (133)149 >. 

This reaction, designed by Gilbert Stork, fosters monoalkylation. Enamines —[see Problem 17.5(a)(5)], of ketones are monoalkylated with reactive halides, such as benzyl and allyl, in good yield at the a C. The enamines are made from the ketone and preferably a 2° amine, RjNH. 

The method is quite useful for particularly active alkyl hahdes, such as allylic, benzyhc, and propargyhc halides, and for a-halo ethers and esters. Other primary and secondary halides can show sluggish reactivity. The react of enamines with benzotriazole derivatives has been reported. Tertiary hahdes do not give the reaction at all since, with respect to the halide, this is nucleophilic substitution and ehmination predominates. The reaction can also be applied to activated aryl halides (e.g., 2,4-dinitrochlorobenzene see Chapter 13), to epoxides, and to activated alkenes, such as acrylonitrile. The latter is a Michael-type reaction (15-24) with respect to the alkene. 

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