Acetoacetate Ester and the Knoevenagel Condensation

As for the coupling of I and 2 mol of II, benzopyranone (I) features three possible sites amenable to nucleophilic attack The two carbonyls and the tri- 

At this point the starred carbon would experience additional electron withdrawal since it would now be in direct conjugation with three carbonyls, once the elimination of water occurs. This condition will increase its chances to override competition from the other three electrophilic centers present in this intermediate (TV) for the second mole of acetoacetic ester anion. The components of the resulting crowded enol ether derivative V are favorably disposed 

Hamish, Justus Liebigs Ann. Chem, 765, 8 (1972) see also A. Nohara, H. Kunki, T. Saijo, K. Ukawa, T. Murata, M. Kanno, and Y. Somo, J. Med. Chem., 18, 34 (1975) and references cited therein. 

The beauty of this reaction lies in the fact that nearly all the facts needed to elucidate the mechanism are, in one way or another, in the products. Although the formation of 11 might seem somewhat tantalizing at first, a second glance will reveal that simply isomerization of I will suffice to account for it. A rather unusual isomerization, however, because activation of the a carbon of the ester as a nucleophile and introduction of formaldehyde (from where ) at this carbon need justification. The first argument may be reformulated as the formation of an ester enolate, which is made possible by the advent of lithium amide superbases such as lithium diisopropyl amide (LDA) in aptotic tetrahydrofuran (THF)-hexamethyl-phosphoramide (HMPA) solvent mixtures.2 The participation of an ester enolate is emphasized by the formation of condensed diester IV. 

Furthermore, by assuming that the methoxy unit maintains its integrity through the reaction, the formaldehyde fragment mentioned earlier must proceed from the oxymethylene unit of I. At this stage it is timely to focus one s attention on product III. It is a dimeric form of dimethyl ketene. This ketene must come from the ester enolate of I (see Problem 21). Therefore, the simultaneous generation of dimethyl ketene VII and formaldehyde is conceivable. 

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