Acylation of ketone enolate

Even though ketones have the potential to react with themselves by aldol addition recall that the position of equilibrium for such reactions lies to the side of the starting materials (Section 18 9) On the other hand acylation of ketone enolates gives products (p keto esters or p diketones) that are converted to stabilized anions under the reaction conditions Consequently ketone acylation is observed to the exclusion of aldol addition when ketones are treated with base m the presence of esters... 

It s reasonable to ask why one would prepare a ketone by way of a keto ester (ethyl acetoacetate, for example) rather than by direct alkylation of the enolate of a ketone. One reason is that the monoalkylation of ketones via their enolates is a difficult reaction to cany out in good yield. (Remember, however, that acylation of ketone enolates as described in Section 21.4 is achieved readily.) A second reason is that the delocalized enolates of (3-keto esters, being far- less basic than ketone enolates, give a higher substitution-elimination ratio when they react with alkyl halides. This can be quite important in those syntheses in which the alkyl halide is expensive or difficult to obtain. 

Against Wastefulness A Practical Hint Regarding the Acylation of Ketone Enolates... 

The protocol described also can be used for the acylation of ketone enolates with carbonic acid derivatives (Figure 13.62). Especially good acylating agents are cyanocarbonic acid methyl ester (Mander s reagent, Figure 13.62, top) and dialkyl pyrocarbonates (bottom). Usually it is not possible to use dimethyl carbonate for the acylation of ketone enolates because dimethyl carbonate is a weaker electrophile than cyanocarbonic acid methyl ester or diethyl pyrocarbonates. 

Fig. 13.62. Acylation of ketone enolates with carbonic acid derivatives. Especially good acylation reagents are cyanocarbonic acid methyl ester (top) and dialkyl pyrocarbonates (bottom).

A carbonic acid derivative which, surprisingly, also proves to be suitable for the acylation of ketone enolates, is Stiles reagent, i.e., (methoxymagnesium) monomethyl carbonate. In Section 8.2, you saw how this reagent can be obtained. Ketone enolates are carboxylatedby Stiles reagent to furnish a /3-keto carboxylic acid, as shown by the reaction equation below. As this keto acid is initially obtained as the (methoxymagnesium) carboxylate, such an acylation can easily proceed without the extra equivalents of enolate or base mentioned above. 

Acylations of ketone enols with anhydrides are catalysed by Lewis acids such as BF3, This process will remind you of Friedel-Crafts acylation but a better analogy is perhaps the aldol reaction where metals such as lithium hold the reagents together so that reaction can occur around a six-membered ring. 

Keto-thionoesters (320) are obtainable by acylation of ketone enolates using a trithiodicarbonate (319) in generally excellent... 

This phenomenon is discernible also during acylation of ketone enolates. The results of acylation of the bromomagnesium salt, generated by conjugate addition of Grignard reagent to benzalacetone (149), indicate a great enhancement of the 0-alkylation product fraction. This is accompanied by depletion of the C-alkylated compound when HMPT is added. 

In many cases, the regioselectivity of the enolate addition (C-O vs C-C bond formation) is a problem [100]. In particular, the site-selective C-acylation of ketone enolates to form P-ketoesters is an important issue in total synthesis. 

The most common transformation involving acylation of ketone enolates is their formylation by reaction with ethyl formate. 

The enolates of ketones can be acylated by esters and other acylating agents. The acylation of ketones is an important method of enhancing reactivity and selectivity in the synthetic modification of ketones. Some examples of the acylation of ketone enolates are shown in Scheme 2.11. The products of these reactions are... 

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