The Stobbe condensation

The condensation of aldehydes and ketones with succinic esters in presence of sodium ethoxide is known as the Stobbe condensation. The reaction with sodium ethoxide is comparatively slow and a little reduction of the ketonic compound to the carbinol usually occurs a shorter reaction time and a better yield is generally obtained with the more powerful condensing agent potassium ieri.-butoxide or with sodium hydride. Thus benzophenone condenses with diethyl succinate in the presence of potassium iert.-butoxide to give a 94 per cent, yield of p-carbethoxy-Yy-diphenylvinylacetic acid (I) is the potassium salt  

A simple application of the reaction may be mentioned. Refluxing of (I) with 48 per cent, hydrobromic acid and glacial acetic acid leads to hydrolysis and decarboxylation and the production of a mixture of the y-lactone yy-di-phenylbutyrolactone (II) and the isomeric unsaturated acid yy-dlphenyl-vinylacetic acid (III) reduction by the Clemmensen method or catalytically 

The Stobbe condensation thus provides a method for introducing a propionic acid residue at the site of a carbonyl group. 

The following mechanism for the reaction has been suggested. It postulates formation of an intermediate paraconic ester (A) the irreversible alkoxide cleavage of this cyclic ester drives the reaction to completion  

Cool the flask in ice, acidify with 10 ml. of cold 1 1-hydro-chloric acid and distil under reduced pressure (water pump) until most of the alcohol is removed. Add water to the residue, extract several times with ether, wash the combined ethereal extracts with N ammonia solution until a test portion gives no precipitate upon acidification. Extract the combined alkaline solutions once with a fresh portion of ether, and add the aqueous solution to an excess of dilute hydrochloric acid the final mixture should still be acidic to Congo red. Collect the crystalline half-ester by filtration at the pump, wash it with water and dry at 100 . The yield is 14-5 g., m.p. 122-125 . Recrystallise by dissolving in about 40 ml. of warm benzene and adding an equal volume of petroleum ether (b.p. 40-60 ) 13-5 g. of the colourless half-ester, m.p. 125-126 , are obtained. 

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Aromatic aldehydes (100), eg, cinnamaldehyde, and ketones (101) react ia a similar manner (eq. 4). Ketones containing reactive methyl or methylene groups give with succiaates, ia the presence of sodium hydride, both the Stobbe condensation and the formation of diketones by a Claisen mechanism (102) (eq. 5). 

The. synthesis starts with the Stobbe condensation of diethylsuccinate and 3,4-dichloroben-zophenone (13). The product (14) is hydrolyzed and decarboxylated to a cis-trans mixture of olefins (15). This last is reduced using a Pd/C catalyst and then undergoes unidirectional Friedel-Crafts intramolecular acylation into the more reactive ring to produce substituted tetralone 16. 

An intriguing rearrangement was reported by Yates (72) during an attempt to carry out the Stobbe condensation. It resulted in the formation of a cyclopropane derivative from 4-benzoyloxycyclohexanone by the (proposed) mechanism shown. 

The Stobbe condensation has been extended to di-rert-butyl esters of glutaric... 

Benzofuran-2-carbaldehydes readily undergo Wittig reactions in tetra-hydrofuran at room temperature with the resonance-stabilized ylide 2-car-boxy-l-methoxycarbonylethyltriphenylphosphorane, affording high yields of ( )-4-(2-benzofuranyl)-3-methoxycarbonylbut-3-enoic acids. This method is preferable to the Stobbe condensation. The Stobbe-type intermediates undergo quantitative cyclization to methyl l-acetoxydibenzofuran-3-carboxylates on exposure to acetic anhydride at 100 C. Examples are shown in Scheme 27. The intermediate 109 has been used in a synthesis of cannabifuran (110), and the intermediate 111 has been used in a synthesis of the lichen metabolite schizopeltic acid (112). ... 

Tetrahydrobenzo[6]thiophen-4-one undergoes the Stobbe condensation with diethyl succinate to give the half-ester (143), hydrolysis of which yields the corresponding diacid.447 Decarboxylation of the diacid affords the spirolactone (144). 

Propose a mechanism that will account for the product of the Stobbe condensation ... 

CH2,CH2,C02Et. From the latter the three-carbon unit of diethyl succinate may be recognised, and the Stobbe condensation is a suitable illustration of this process. Thus the reaction of aldehydes or ketones with succinic esters in the presence of potassium t-butoxide (or with sodium hydride) gives alkylidene-succinic acid esters (25). The reaction is somewhat slower in the case of the less basic sodium ethoxide. 

The Stobbe condensation was reviewed by Johnson and Daub in 1951.5 They postulated the formation of a lactonic ester as an intermediate (see Scheme 2). The base-induced elimination of the lactonic ester led to the regiospecific formation of the half-ester, which is esterified to yield compound 2. 

This is an example of the Stobbe condensation reaction and is discussed (1). 

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