Enamine alkylations

Enamines, like enolate anions, are ambient nucleophiles. Alkylation at nitrogen is sometimes a competing reaction. The product of A -alkylation, after hydrolysis, leads to recovery of starting ketone. 

Alkylation of enamines requires relatively reactive alkylating agents, such as methyl iodide, benzyl halides, a-haloketone, a-haloesters, and a-haloethers. Enamines react efficiently with electrophilic olefins by conjugate addition, an aspect of their chemistry which will be described in Section 1.10. 

The nitrogen analogs of enolate ions, referred to as metalloenamineSy can be prepared by deprotonation of imines  

Just as enamines are more nucleophilic than enols, metalloenamines are more nucleophilic than enolate anions and react efficiently with alkyl halides. One useful application of metalloenamine chemistry is that it permits a-alkylation of aldehydes. 

SECTION 1.9. THE NITROGEN ANALOGS OF ENOLS AND ENOLATES— ENAMINES AND METALLOENAMINES 

Because of the predominance of the less substituted enamine, alkylations occur 

The nitrogen analogs of enolate ions can be prepared from imines and strong bases. The resulting anions are alkylated by alkyl halides  

Such alkylation procedures are found to give alkylation primarily on the less hindered carbon in unsymmetrical ketones.  

Enamine chemistry is also the basis for the synthetic utility of dihydrooxazine derivatives. The quaternary salt 5 is converted to the cyclic enamine 6 on reaction with sodium hydride. Aldehydes are obtained after reduction and hydrolysis of the alkylation product.  

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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). 

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. 

Extensions of the enamine alkylation to a-tetralones have also been used (245-248), but product yields were lower, presumably due to steric crowding in a transition state where generation of an imonium salt gives rise to a repulsion between a methylene group on nitrogen and a peri aromatic proton. 

Other interesting synthetic applications of the ketone-derived enamine alkylation are found in the monomethylation of steroid enamines (249), extension of the benzylation reaction (250) to a ferrocene derivative (251), the use of a-bromoesters (252) and ketones (252) or their vinylogues (25J), in the syntheses of alantolactone (254-256), isoalantolactone (257), and with a bridged bis-enamine (258). The use of bifunctional alkylating agents is also seen in the introduction of an acetylenic substituent in the synthesis of the characteristic fragrant constituent of jasmine (259), the synthesis of macrocyclic ketolactones (260), the use of butyrolactone (261), and the intermolecular or intramolecular double alkylations of enamines with dihalides (262). 

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 related enamine alkylation is seen in the rearrangement of an ethylene imine vinylogous amide, which was heated with sodium iodide in diglyme. The presumed internal enamine alkylation constitutes a critical step in an oxocrinane synthesis (265). Use of an ethylene imine urethane for alkylation of an enamine and formation of the hexahydroindole system has also been reported (266). 

Alkylation of enamines with epoxides or acetoxybromoalkanes provided intermediates for cyclic enol ethers (668) and branched chain sugars were obtained by enamine alkylation (669). Sodium enolates of vinylogous amides underwent carbon and nitrogen methylation (570), while vicinal endiamines formed bis-quaternary amonium salts (647). Reactions of enamines with a cyclopropenyl cation gave alkylated imonium products (57/), and 2-benzylidene-3-methylbenzothiazoline was shown to undergo enamine alkylation and acylation (572). A cyclic enamine was alkylated with methylbromoacetate and the product reduced with sodium borohydride to the key intermediate in a synthesis of the quebrachamine skeleton (57i). 

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. 

The formation of 3-acylpyridinium compounds (59/) from primary amines and l-methoxybutene-3-one can be regarded as the enamine alkylation of a vinylogous amide followed by cyclization and loss of methanol and water. 

In the reaction of 2-chlorocyclohexanone with a secondary amine (632) one encounters an intramolecular enamine alkylation analogous to the internal alkylations which constitute the critical step of some Favorskii rearrangements. 

Owing to the predominance of the less-substituted enamine, alkylations occur primarily at the less-substituted a-carbon. Synthetic advantage can be taken of this selectivity to prepare 2,6-disubstituted cyclohexanones. The iminium ions resulting from C-alkylation are hydrolyzed in the workup procedure. 

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... 

Alkylation of enamines requires relatively reactive alkylating agents for good results. Methyl iodide, allylic and benzylic halides, a-haloesters, a-haloethers, and a-haloketones are the most successful alkylating agents. Some typical examples of enamine alkylation reactions are shown in Scheme 1.10. 

In an enamine alkylation study, piperitone (8 X = H) gave, in addition to the expected dienamines, two rearranged dienamines via ring opening and reclosure hydrolysis yielded the o-menthenones (181Dauben s full paper (Vol. 7, p. 34) on... 

Problem 17.43 Show how acetone can be converted into 4-phenyl-2-butanone using enamine alkylation. M... 

Step 1 Enamine alkylation followed by iminium ion hydrolysis. 

For subsequent transformations, it was necessary to protect the amino and C-2 carboxyl groups of fra/w-4-hydroxy-L-proline 34. Throughout all of the synthetic work to be described, A-benzoyl amide protection was chosen as it was felt likely that such a functional group would be resistant to most reaction conditions. Initially, a C-2 terf-butyl ester was chosen in an attempt to maximize the stereoselectivity in the planned enamine alkylation reaction however, later experiments revealed that the more straightforward to introduce C-2 methyl ester was equally effective. The preparations for all of the derivatives used are described here. 

Initiated by Stork and co-workers,47 the scope and stereochemistry of enamine alkylations have been well explored. In general, good stereoselectivities can be obtained using bulky directing groups, polar aprotic solvents, and low temperatures. 

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