γ-Alkylation of 1,3-dicarbonyl compounds

1,3-Diketones and keto aldehydes undergo the typical condensations at the methylene group between the two carbonyl groups. However, it was discovered in 1958 that if these compounds are treated with two equivalents of base, a disalt is formed that undergoes alkylation or other carbon–carbon condensations at the γ carbon rather than at the methylene group.

Acetylacetone with one equivalent of sodium amide gives the monoanion, which is methylated at the alpha carbon; with two equivalents it gives the dianion, which is methylated at the gamma carbon

The discovery is due to Charles R. Hauser and Thomas M. Harris. In general, the reaction can be carried out with substituted 1,3-diketones, 1,3-dialdehydes or β-keto esters:

A 1,3-dicarbonyl compound with two equivalents of sodium amide and an alkyl halide is alkylated at the gamma carbon; R1 can be H, alkyl, aryl or an ester

Some examples with benzoylacetone; an important limitation is that the electrophilic species reacting with the double carbanion must have no acidic hydrogens:

The benzoylacetone dianion reacts at the gamma carbon with carbon dioxide, ethyl benzoate, furfuryl bromide, benzophenone and phenyl vinyl ketone

Structure of the dianion

The dianion can be represented by four resonance forms, of which the one in red should be the main contributor, as it explains the reactivity at the γ carbon: the terminal carbanion is the least stabilized and therefore the most nucleophilic.

Four resonance forms of the dianion of a 1,3-diketone; the form in red has the charge on the gamma carbon and an enolate in the rest of the molecule

¹H NMR supports a planar structure of the dianion, because it gives two different signals for the terminal hydrogens, and the small coupling constant between them is compatible with a terminal olefin-like structure.

Simulated proton nuclear magnetic resonance spectrum of the benzoylacetone dianion, with two doublets for the terminal hydrogens 14 and 15

Influence of the counterion

The counterion of the dianion is sometimes very important for the outcome of the reaction. Lithium usually allows the use of electrophiles bearing acidic hydrogens: carbon–carbon bond formation is sometimes faster than ionization of the ester. With potassium, by contrast, the dianion deprotonates the ester:

The dilithium dianion of benzoylacetone is acylated by ethyl propanoate; the dipotassium one deprotonates the ester and gives no acylation product

Regioselectivity

When the diketones are unsymmetrical, alkylation or acylation is usually quite regioselective: the second proton is removed from the more acidic γ carbon, and between two alkyl positions a methyl is preferred to a methylene and a methylene to a methine. Some examples:

Four unsymmetrical diketones methylated through the dianion; the major product results from alkylation at the methyl, the methylene or the benzylic position, depending on the case

1,3-Keto aldehydes

The alkylation of 1,3-keto aldehydes is interesting because the aldehyde can be removed in a final step of basic hydrolysis (a retro-Claisen). The formyl group thus acts as a temporary activating and protecting group that directs the alkylation of a ketone to the position that would not be alkylated directly. Look at the different outcome of these two procedures with 1-decalone:

1-Decalone with sodium amide and methyl iodide is methylated at C2. If it is first formylated with ethyl formate, the keto aldehyde dianion is methylated at the ring-fusion position and basic hydrolysis removes the formyl group

A synthesis example

The methyl acetoacetate dianion