Malonic acid: Doebner reaction with

Condensation of thiophene-3-carbaldehyde 38 with malonic acid (Doebner reaction) in a mixture of pyridine (Py) and piperidine (Hp) with heating affords ( )-3-(3-thienyl)acrylic add (42), whose treatment with thionyl chloride in Py produces 3-chlorothieno[2,3-6]thiophene-2-carboxylic add chloride (43) (72ACS2982,... 

This preparation is another example of the condensation of an aldehyde with malonic acid and pyridine to 3neld ultimately an ap-unsaturated acid (Doebner reaction). It is included here because, unlike the acids prepared from many of the lower aUphatic aldehydes, the product consists largely (about 95 per cent.) of the ap-isomeride and only about 5 per cent, of the PY-isomeride is present ... 

The so-called Doebner reaction condenses malonic acid and pyridine with an aldehyde such as benzaldehyde. Draw the product and suggest a mechanism for this reaction. 

Ootonic acid may be prepared by condensing acetaldehyde with malonic acid in pyridine solution in the presence of a trace of piperidine (Doebner reaction see discussion following Section IV,123). 

Sorbic acid is prepared by the condensation of crotonaldehj de with malonic acid ill the presence of pyridine at 100° (Doebner reaction) ... 

Higher-molecular-weight normal 2-alkenoic acids have been prepared in poor yields by the Doebner condensation of aldehydes with malonic acid,5-7 and by the Reformatsky reaction of aldehydes with ethyl bromoacetate followed by dehydration.8 The a-iodo acid, prepared from the bromo acid, has been dehydrohalogenated with potassium hydroxide in ethanol,9 but large quantities of the a-hydroxy acid are formed as a by-product which is difficult to separate in some instances. The present procedure is an adaptation of a published method.6... 

The methylene groups of hippuric acid and malonic acid are much more reactive than that of acetic acid. They may be caused, therefore, to condense with aldehydes under much milder conditions, e.g. by the action of pyridine. The use of malonic acid forms an extension of Perkin s reaction to the aliphatic series (Doebner), e.g. 

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. 

Simple aliphatic aldehydes and ketones cannot be used as the carbonyl component in the Perkin reaction. Knoevenagel5 reported the successful condensation of aldehydes and ketones with malonic acid in the presence of ammonia or amines. The most satisfactory method uses pyridine as a catalyst and is known as the Doebner modification.6 Thus, acetaldehyde 18 reacts with malonic acid (19) in the presence of a pyridine catalyst to afford the acid 20 in 60% yield. 

When malonic acid is used as the enolate partner, with pyridine as the base, the condensation reaction with aldehydes is known as the Doebner condensation. This is an important route to non-a-amino acids. An example of this condensation when... 

An earlier version of this reaction condensed 4.18 and malonic acid to give 4.19. Refluxing 4.19 led to the monomer 4.20), which decarboxylated under the reaction conditions to give 3-amino-3-phenylpropanoic acid, 4.21. Doebner condensation with malonic acid itself sometimes leads to very poor yields of product, as seen above. An improvement in the reaction used nitro-ester 4.22 rather than malonic acid, and 4.23 [ethyl 3-(N-phenylamino)-2-nitroprop-2E-enoate] was produced in good yield. 

A novel route to labelled a,/3-unsaturated acids is the Doebner reaction between aldehydes and [O, 0 - H2]malonic acid which gives the expected acid with deuterium at the a-position. Condensation with a,j8-unsaturated aldehydes leads to dienoic acids labelled at both the a- and the -y positions. 

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