A retrosynthesis of the diketone known as dimedone. The functionality suits disconnections that use enolate and conjugate addition routes.
Retrosynthetic analysis of dimedone shows that there is both a 1,3-difunctional and 1,5-difunctional relationship between the two carbonyl functional groups. The 1,3-diX relationship naturally lends itself to aldol chemistry using enolates as the nucleophile. 1,5-diX relatiionships are frequently constructed by using conjugate addition (also known as Michael addition or 1,4-addition).
Both of these chemistries rely on being able to form the enolate nucleophile by tautomerisation of the parent carbonyl. This converts the usually electrophilic carbonyl group an alternative reactivity mode as a nucleophile in the alpha-position. The pKa of the proton adjacent to a carbonyl is roughly 20 and so can be deprotonated reversibly by alkoxide bases, such as sodium ethoxide. If a there is a proton between two carbonyl groups, the enolate formed is much more easy to form as it can delocalise its negative charge and so these motifs have a pKa closer to 10. This more stable conjugated enolate acts as a soft nucleophile and is well matched for conjugate addition (Michael addition) reactions where the beta-position of an alpha,beta-unsaturated carbonyl is a soft electrophile. A cheap and readily available 1,3-dicarbonyl that is often used as a soft d2 synthon in organic synthesis is the malonate diester, derived from malonic acid.
Using a malonate-derived enolate in synthesis often leads to a future step involving decarboxylation to remove excess functionality. In this synthesis of dimedone, a beta-ketoester is formed as a key intermediate, which can be saponified to the beta-ketoacid. A pericyclic (group transfer) reaction is initiated at high temperature to extrude carbon dioxide. This decarboxylation is thermodynamically favourable due to the increase in entropy in such a reaction associated with the release of a gas.
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