Acetoacetic ester synthesis retrosynthetic analysis

For retrosynthetic analysis, a carboxylic acid with one or two aUgrl groups bonded to the a-carbon is a characteristic product of the acetoacetic ester synthesis starting with diethyl malonate. 

The preparation of (83) (Expt 8.29) is an example of the Hantzsch pyridine synthesis. This is a widely used general procedure since considerable structural variation in the aldehydic compound (aliphatic or aromatic) and in the 1,3-dicarbonyl component (fi-keto ester or /J-diketone) is possible, leading to the synthesis of a great range of pyridine derivatives. The precise mechanistic sequence of ring formation may depend on the reaction conditions employed. Thus if, as implied in the retrosynthetic analysis above, ethyl acetoacetate and the aldehyde are first allowed to react in the presence of a base catalyst (as in Expt 8.29), a bis-keto ester [e.g. (88)] is formed by successive Knoevenagel and Michael reactions (Section 5.11.6, p. 681). Cyclisation of this 1,5-dione with ammonia then gives the dihydropyridine derivative. Under different reaction conditions condensation between an aminocrotonic ester and an alkylidene acetoacetate may be involved. 

A convenient way to determine when to apply the acetoacetic ester or malonic ester approach to a synthetic problem is to incorporate the synthon concept into retrosynthetic analysis. A synthon is a structural unit in a molecule that is related to a synthetic operation. A CH2CO2H group is a synthon that alerts us to the possibility of preparing a target by a malonic ester synthesis. Likewise, a CH2C(0)CH3 group is a synthon that suggests an acetoacetic synthesis. 

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