Alkylation, enolate ions Amides

Ketones, esters, and nitriles can all be alkylated using LDA or related dialkyl-amide bases in THE. Aldehydes, however, rarely give high yields of pure products because their enolate ions undergo carbonyl condensation reactions instead of alkylation. (We ll study this condensation reaction in the next chapter.) Some specific examples of alkylation reactions are shown. 

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. 

The tendeney towards reaetion at the center with the maximum eleetron density inereases when dipolar non-HBD solvents are employed owing to the laek of speeifie solvation cf. solvents HCON(CH3)2 and CH3SOCH3 in Table 5-22). Thus, in the alkylation of the enolate ions of 1,3-dicarbonyl compounds, the greatest yields of the 0-alkylated isomers are obtained in hexamethylphosphoric triamide, followed by dipolar non-HBD solvents of the amide type [372-375]. 

Many highly branched ketones have been prepared by the alkylation of simpler ketones, sodium amide or sodium alkoxides generally being used to form the enolate ion. For example, ketones of the type RCOR j where R and R represent many combinations of methyl (Me), ethyl (Et), n-propyl (Pr), isopropyl, w-butyl, s-butyl, t-butyl, isoamyl, EtjCH—,... 

The most general method of preparation for tr amino adds is the ainido mslonatc synthesis, a straigbtforweird extension of the malonk ester syn thesis (Section 22.8). The reaction begins with conversion of diethyl Hcetamidomalonate into an enolate ion by treatment with base, followed tiy 3 2 alkylation with a primary alkyl halide. Hydrolysis of both the amide protectii group and the esters occurs when the alkylated product is warmed with aqueous add, and decarboxylation then takes place to yield an a-add. For example, aspartic add can be prepared irom ethyl bromoacetate ... 

Subsequent research showed the SrnI mechanism to occur with many other aromatic compounds. The reaction was found to be initiated by solvated electrons, by electrochemical reduction, and by photoinitiated electron transferNot only I, but also Br, Cl, F, SCeHs, N(CH3)3, and 0P0(0CH2CH3)2 have been foimd to serve as electrofuges. In addition to amide ion, phosphanions, thiolate ions, benzeneselenolate ion (C HsSe"), ketone and ester enolate ions, as well as the conjugate bases of some other carbon acids, have been identified as nucleophiles. The SrnI reaction was observed with naphthalene, phenanthrene, and other polynuclear aromatic systems, and the presence of alkyl, alkoxy, phenyl, carboxylate, and benzoyl groups on the aromatic ring does not interfere with the reaction. ... 

For acylations with reactive esters, such as formate or oxalate (see Section 3.6.4.5), sodium alkoxides are still the bases of choice, but sodium hydride, dimsyl sodium, sodium or potassium amide or sodium metal have all been used for the in situ generation of the enolate anion. A typical example is shown in Scheme 47. Acylation by esters results in the production of 1 equiv. of the alkoxide ion, along with the p-dicarbonyl compound proton transfer then results in the production of the conjugate base of the dicarbonyl compound. This process normally leads to the more stable anion in the acylation of an unsymme-trical ketone. The acyl group thus becomes attached to the less-substituted a-position of the ketone. The less stable 0-acylated products are normally not observed in such reversible base-catalyzed reactions. Methyl alkyl ketones are normally acylated on the methyl group where both a-carbons are substituted to the same extent, acylation occurs at the less-hindered site. Acylation is observed only rarely at a methine carbon as the more stable p-diketone enolate cannot be formed. 

Stereoselective aldol reactions are limited by their ability to obtain stereoisomerically pure ( )- or (Z)-enolates separately, and it has been suggested that equilibration may be occurring to erode the enolate selectivities. However, it would appear that the measured rate of enolate equilibration appears to be too low to be much of an influence.It was suggested by Ireland in 1976 that LDA-mediated enolizations may proceed by cycUc transition states via disolvated LDA monomers. Tbis mecbanism bas since been widely cited for its predictive power. Ireland proposed that the deprotonation process may be proceeding via one of two proposed transition states, where proton transfer is synchronous with metal ion transfer. Non-bonded interactions between amide alkyl groups and the enolate alkyl group cause a preference for E-enolate formation (Scheme 1, refs 124,136). 

In the presence of a very strong base, such as amide ion or an organolithium reagent, it is possible to convert dicarbonyl compounds to their dianions. Subsequent alkylation of such dianions leads to alkylation at the more strongly basic enolate site, rather than at the carbon atom between the two carbonyl carbons. The more acidic methylene group activated by two carbonyl substituents is the preferred site in the monoanion, as discussed earlier. The ability to determine the site of monoalkylation by choice of the amount and nature of the basic catalyst has significantly expanded the synthetic utility of enolate alkylations. Scheme 1.7 gives some examples of formation and alkylation of dianions. 

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