Malonate anion, reaction with aldehydes

This reaction type leading to oc,/ -unsaturated acids and esters is exemplified in the Perkin reaction (Section 6.12.3, p. 1036) and the Knoevenagel reaction (Section 5.11.6, p. 681). The Doebner reaction, which is illustrated in this section, is the condensation of an aldehyde with malonic acid in pyridine solution, often in the presence of a trace of piperidine. The reaction mechanism involves the addition of a malonate anion to the aldehydic carbonyl carbon atom followed by the elimination of water accompanied by decarboxylation. 

Reactions which may at first glance appear to involve ylides may not in fact do so. For example, a bromomalonic ester reacted with a variety of aldehydes in the presence of tributylarsine to form alkylidene- or arylidene-malonic esters, but no base was required and it was suggested that reaction proceeded not via an ylide but via an arsonium salt formed by extraction of a bromonium ion from the malonic ester The malonate anion... 

Malonic esters can be converted to the enolate anion and condensed with aldehydes, ketones, or acid derivatives. The reaction of malonic acid with an aldehyde using pyridine as a base is called the Knoevenagel condensation. 

The intra-molecular Claisen condensation is called a Dieckmann condensation, and it generates a cyclic compound 58,99,101,118. Malonic esters can be converted to the enolate anion and condensed with aldehydes, ketones, or add derivatives. The reaction of malonic acid with an aldehyde using pyridine as a base is called the Knoevenagel condensation 59, 60, 61, 62, 69, 99,108,110,112, 113,119,124. 

This process represents a Knoevencigel condensation,3 a reaction in which a compound with an acidic methylene group, such as dimethyl malonate (8). condenses with a carbonyl compound like citronellal (9) to give an alkene. Reaction occurs in a weakly basic or neutral medium. Catalytic amounts of piperidinium acetate suffice to deprotonate malonic ester 8. The resulting anion 15 adds to the aldehyde citronellal (9) to give alkoxide 16. 

Intramolecular asymmetric Stetter reactions enjoy a range of acceptable Michael acceptors and acyl anion precursors. These reactions can utilize aromatic, heteroaromatic, and aliphatic aldehydes with a tethered a,p-unsaturated ester, ketone, thioester, malonate, nitrile, or Weinreb amide. In this part, we will give a brief summary about asymmetric intramolecular Stetter reactions and selected recent results in this area (Scheme 7.17). 

The reaction of diethyl malonate (90) with sodium hydride generates enolate anion 91 as the conjugate base, and hydrogen gas is the conjugate acid. It has the three resonance contributors shown in the illustration, although 91A has the highest concentration of electron density, and 91 will react as a carbanion nucleophile. There is one extra resonance form in the malonate enolate anion relative to a simple ester due to the second carbonyl unit, and it means that 91 is more stable than the enolate derived from a monoester. In part, this accounts for the enhanced acidity and easier formation of the enolate anion using a weaker base. Once formed, 91 is a carbon nucleophile and it will react with both aldehydes and ketones, as well as with other esters. 

If we consider the synthesis of 20.18, we first note that it is a 1,5-dicarbonyl compound—the disconnection that we need is suggested by the ring—as in many other examples, we disconnect the bond exocyclic to the ring. The synthon for "[CH2COOH] is the anion of diethyl malonate, and the forward reaction is shown in Figure 20.34. Some other synthetic examples are shown in Figure 20.35. In the first example, only one component is able to enolize, and the enolate is stabilized by the phenyl ring. However, the aldehyde is more electrophilic than the ketone. The second example is a reminder that any a,p-unsaturated carbonyl compound will react in this way with any stabilized enolate-type anion. The final example was used in a synthesis of cholesterol it proceeds via the most stable enolate. 

In discussing the above reactions, we emphasized the effect of the basic catalyst on the a-H atoms of the carbonyl compoimds (i.e., carboxy anhydrides and malonic esters). The resulting anions accelerated the formation of the end products of these reactions. The anions were shown to react with an aldehyde containing no a-H atoms (equations 12 and 17). 

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