Decarboxylation with 3-keto esters

Suggestions as to the methods for identifying the above classes of compounds will be found under Class Reactiona in Section XI,7. Some fimther remarks upon enolic compounds (see Table IV,1I4A) may be made here. Enols may be divided into (a) p-keto esters and (b) 1 3-diketones. With 5 per cent, sodium hydroxide solution, a p-keto ester yields the salt of the corresponding acid, which when heated with dilute hydrochloric acid is decarboxylated to a ketone ... 

The decarboxylation of allyl /3-keto carboxylates generates 7r-allylpalladium enolates. Aldol condensation and Michael addition are typical reactions for metal enolates. Actually Pd enolates undergo intramolecular aldol condensation and Michael addition. When an aldehyde group is present in the allyl fi-keto ester 738, intramolecular aldol condensation takes place yielding the cyclic aldol 739 as a main product[463]. At the same time, the diketone 740 is formed as a minor product by /3-eIimination. This is Pd-catalyzed aldol condensation under neutral conditions. The reaction proceeds even in the presence of water, showing that the Pd enolate is not decomposed with water. The spiro-aldol 742 is obtained from 741. Allyl acetates with other EWGs such as allyl malonate, cyanoacetate 743, and sulfonylacetate undergo similar aldol-type cycliza-tions[464]. 

The sequence begins with a Claisen condensation of ethyl pentanoate to give a p keto ester The ester is hydrolyzed and the resulting p keto acid decarboxylates to yield the desired ketone... 

The anion of a p keto ester may be alkylated at carbon with an alkyl halide and the product of this reaction subjected to ester hydrolysis and decarboxylation to give a ketone... 

The three-step sequence of 0) enolate ion formation, (2) alkylation, and (3) hydrolvsis/decarboxylation is applicable to all /Tketo esters with acidic a hydrogens, not just to acetoacetic ester itself. For example, cyclic /3-keto esters such as ethyl 2-oxocycIohexanecarboxylate can be alkylated and decarboxy-lated to give 2-substituted cyclohexanones. 

A-Unsubstituted isoxazolidines such as 65 undergo facile decarboxylative peptide couplings with a-keto acids <06JA1452>. The use of water as solvent or cosolvent was particularly beneficial for the formation of amides in high yields. The methyl a-keto esters obtained could be saponified to the corresponding a-keto acids, and the (i-peptide chain could then be extended by reaction with another isoxazolidine. 

Method D (hydrolysis and decarboxylation of malonic esters and fi-keto esters) LiBr (1.73 g), TBA-Br (0.32 g, 1 mmol), the malonic ester or p-keto ester (10 mmol) and H20 (360 ml) are subjected to microwave irradiation for 15 min. The cooled mixture is extracted with EtOAc (50 ml) and the organic solution is filtered through Florisil and evaporated to yield the decarboxylated compound. 

Ethyl 3-oxoalkanoates when not commercially available can be prepared by the acylation of tert-butyl ethyl malonate with an appropriate acid chloride by way of the magnesium enolate derivative. Hydrolysis and decarboxylation in acid solution yields the desired 3-oxo esters [59]. 3-Keto esters can also be prepared in excellent yields either from 2-alkanone by condensation with ethyl chloroformate by means of lithium diisopropylamide (LDA) [60] or from ethyl hydrogen malonate and alkanoyl chloride usingbutyllithium [61]. Alternatively P-keto esters have also been prepared by the alcoholysis of 5-acylated Mel-drum s acid (2,2-dimethyl-l,3-dioxane-4,6-dione). The latter are prepared in almost quantitative yield by the condensation of Meldrum s acid either with an appropriate fatty acid in the presence of DCCI and DMAP [62] or with an acid chloride in the presence of pyridine [62] (Scheme 7). 

The present case simply illustrates another utility of the ester cleavage reaction, i.e., the cleavage of a /3-keto ester with con-ccanitant decarboxylation under only slightly basic conditions. The method should be particularly applicable to systems which are prone to undergo reverse Claisen reactions. 

The advantage of these reaction conditions became more obvious with the enyne 11, in which the reacting olefin is attached to an electron-withdrawing substituent. As mentioned earher, the decarboxylation product 21 of the initially formed keto ester 21 was the major product, due to the prolonged reaction time (Eq. 3). Gratifyingly, when the reaction was carried out under a reduced pressure of CO, the reaction time was significantly reduced to facilitate the isolation of the keto ester 21 as the major product (Eq. 9). 

The majority of publications on transesterification catalyzed by solid acids have focused on the reaction of 3-keto esters. Transesterification provides an alternative route to synthesize these kinds of esters since direct preparation from P-keto acids is not a good option given that they can easily undergo decarboxylation. Table 11 provides a review of results in the literature relating to the transesterification of P-keto esters with alcohols. 

The submitters state that ethyl enanthylsuccinate can be hydrolyzed and decarboxylated to 7-oxocapric acid. The reaction is carried out by heating 57 g. of the keto ester with a solution of 140 ml. of concentrated sulfuric acid in 250 ml. of water. The mixture is stirred while the ethanol is removed gradually by distillation over a period of 3 hours. The acid is taken up in benzene, extracted from the benzene with aqueous alkali, and liberated from the alkaline solution by acidification with concentrated hydrochloric acid. After recrystallization from 50% ethanol about 29 g. (78% yield) of 7-oxocapric acid is obtained as colorless crystals, m.p. 69-70°. 

Spiroannelation. A new method for intramolecular spirocyclizalion involves decarboxylation of w-halogeno-j8-keto esters with lithium chloride in HMPT at 125— 140°. The method appears to be fairly general.1 Examples ... 

In the presence of a basic catalyst, unsaturated esters react with diethyl oxalate to form an unsaturated 5-keto ester in a synthesis of type (iii) (Scheme 99). In many cases these compounds cyclize spontaneously to the substituted pyranone, but where this is not so, ring closure usually follows hydrolysis under acidic conditions. The pyrancarboxylic acids undergo ready thermal decarboxylation (41JOC566). 

Asymmetric hydroboration.1 The key step in a synthesis of natural (+ )-hir-sutic add-C (1), based on an earlier synthesis of racemic 1, is an efficient asymmetric hydroboration of the meso-alkene 2. Reaction of 2 with (+ )-diisopinocampheyl-borane (90% ee) followed by oxidation provides the exo-alcohol 3 in 73% yield and in 92% optical purity. Ring expansion of the corresponding ketone with ethyl diazoacetate is not regioselective even in the presence of BF3 etherate or (C2H5)30+ BF4, but does afford the desired a-keto ester in the presence of SbCl5 (8, 500-501). Decarboxylation of the crude product gives (— )-4 in 90% ee after chromatography. 

Pimetic Acid. This acid is manufactured by Tateyama Chemical Company in Japan in quantities of about 100(1-200(1 kg/yr. and by Heinrich Mock Nachf in Germany. The method or process they are using lias not been disclosed. Pimelic acid is available in small quantities with purities of 98% from laboratory chemical supply companies. The preparation of pimelic acid has been described in Organic Syntheses cyclohexanone condenses with diethyl oxalate, followed by decarboxylation in ethyl 2-keto-hcxahydmhcnzoatc, and then eleavage of the fl-keto ester with strong alkali. 

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