Dimedone Claisen condensation

In 1887, Claisen and Lowman reported that the condensation of 2 mol of an ester, such as ethyl acetate, in the presence of base gave the p-keto ester, ethyl acetoacetate (ethyl 3-oxobutanoate equation 1). The intramolecular equivalent was recognized by Dieckmann in 1894. He found that heating an adipic acid ester with sodium and a trace of alcohol led to cyclization, with the formation of a cyclopentanone (equation 2). The reaction was, at an early stage, extended to the acylation of ketones. Claisen himself reported the base-catalyzed reaction of acetophenone and ethyl benzoate to give dibenzoylmethane in 1887. This reaction, too, has an intramolecular parallel. The acylation of ketones with esters and other acid derivatives is sometimes called a Claisen condensation, although this usage is criticized by some writers and avoided by others. A widely used example of ketone acylation is the synthesis of a-formyl (hydroxymethylene) ketones (equation 3). Intramolecular variants of this reaction include the classical synthesis of dimedone (Scheme 1). 

The synthesis of alicyclic 1,3-diketones from 7- or 6-keto esters is a well-established reaction. Over SO examples are tabulated in the 1954 chapter in Organic Reactions, and a similar number are tabulated as involving a Michael addition of a diester or keto ester to an unsaturated ketone followed by a Claisen condensation. These latter reactions involve such well-known syntheses as that of dimedone (S,S-di-methylcyclohexane-l,3-dione Scheme 75). 

It is of interest to note that the preparation of dimethyldihydroresorcinol also named dimedone and methone Section VII,15) involves an initial Michael addition to mesityl oxide, followed by an internal Claisen condensation. 

The compound (III) can however lose ethanol by an internal Claisen ester condensation (p. 264) to give the cyclohexane derivative (IV), which, being the ester of a (3-keto acid, in turn readily undergoes hydrolysis and decarboxylation to give 5,5Hiimethyl cyclohexan-i,3Hiione (V) or Dimedone, a valuable reagent for the detection and estimation of formaldehyde. 

Frequently the basic conditions used cause the initial Michael adduct to undergo intramolecular transformations, as for example in the synthesis of dimedone (Expt 7.11). This involves a Michael reaction between mesityl oxide and diethyl malonate followed by an internal Claisen ester condensation. 

The first enol you saw at the start of Chapter 21 was the stable enol of dimedone , 5,5,-dimethyl-cydohexa-l,3-dione. This six-membered ring is made by a close analogue of the Robinson annelation. The only difference is in the cyclization step, which is a Claisen ester condensation rather than an aldol reaction. 

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