Alkylation, enolate ions Amines

This section deals with the alkylation reactions of such enolates. In the presence of strong bases, amides carrying at least one a-hydrogen 1 can be deprotonated to form enolate ions which, on subsequent alkylation, give alkylated amides. Further reaction, e g., hydrolysis or reduction, furnishes the corresponding acids or primary alcohols, respectively. The pKa values for deprotonation are typically around 35 (extrapolated value DMSO3 7) unless electron-withdrawing substituents are present in the a-position. Thus, deprotonation usually requires non-nucleophilic bases such as lithium diisopropylamide (extrapolated 8 pKa for the amine in DMSO is around 44) or sodium hexamethyldisilazanide. 

A milder alternative to direct alkylation of enolate ions is the formation and alkylation of an enamine derivative. An enamine (a vinyl amine) is the nitrogen analogue of an enol. The resonance picture of an enamine shows that it has some carbanion character. 

Instead of alkyl halides other electrophiles, such as imines or iminium ions, are also used for the nucleophilic attack of enolates. Primary amines react with aldehydes and ketones to produce imines °. For example, the reaction of acetophenone with methyl amine gives... 

Secondly, the Mannich products can be converted to enones. The most reliable method for making the enone is to alkylate the amine product of the Mannich reaction with Mel and then treat the ammonium salt with base. Enolate ion formation leads to an ElcB reaction rather like the dehydration of aldols, but with a better leaving group. 

Other alkylation reactions are observed in the condensation of cyclo-propanium ions (generated in situ) with ketones 89.92)> enamines6, nitroalkanes 93>, dimethylmalonate 92>, and phenol. 92> Thus, 7-hydroxy-7-pyrrolidinobicyclo[4.1.0]heptane (56) as well as the 7,7-dipyrrolidino derivative (54) react with acetone to give the amino ketone 113. 89> This reaction may be pictured as an addition of the enol form of the ketone to the reactive iminium salt formed from the carbinol amine. In like manner, phenol undergoes ortho substitution with the carbinol amine 114 formed from cyclopropanone and dimethyl amine. 

Nucleophilic attack on ( -alkene)Fp+ cations may be effected by heteroatom nucleophiles including amines, azide ion, cyanate ion (through N), alcohols, and thiols (Scheme 39). Carbon-based nucleophiles, such as the anions of active methylene compounds (malonic esters, /3-keto esters, cyanoac-etate), enamines, cyanide, cuprates, Grignard reagents, and ( l -allyl)Fe(Cp)(CO)2 complexes react similarly. In addition, several hydride sources, most notably NaBHsCN, deliver hydride ion to Fp(jj -alkene)+ complexes. Subjecting complexes of type (79) to Nal or NaBr in acetone, however, does not give nncleophilic attack, but instead results rehably in the displacement of the alkene from the iron residue. Cyclohexanone enolates or silyl enol ethers also may be added, and the iron alkyl complexes thus produced can give Robinson annulation-type products (Scheme 40). Vinyl ether-cationic Fp complexes as the electrophiles are nseful as vinyl cation equivalents. ... 

The previous sections have dealt primarily with reactions in which the new carbon-carbon bond is formed in an Sn2 reaction between the nucleophilic carbon species and the alkylating reagent. There is another general and important method for alkylation of carbon that should be discussed at this point. This reaction involves the addition of a nucleophilic carbon species to an electrophilic multiple bond. The reaction is applicable to a wide variety of enolates and enamines. The electrophilic reaction partners are typically a,j8-unsaturated ketones, esters, or nitriles, but other electron-withdrawing substituents also activate the carbon-carbon double bond to nucleophilic attack. The reaction is called either the Michael reaction or conjugate addition The process can also occur with other nucleophiles, such as alkoxide ions or amines, but these reactions are outside the scope of the present discussion. 

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